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1
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Holland AM, Jehoul R, Vranken J, Wohl SG, Boesmans W. MicroRNA regulation of enteric nervous system development and disease. Trends Neurosci 2025; 48:268-282. [PMID: 40089421 PMCID: PMC11981837 DOI: 10.1016/j.tins.2025.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 02/04/2025] [Accepted: 02/18/2025] [Indexed: 03/17/2025]
Abstract
The enteric nervous system (ENS), an elaborate network of neurons and glia woven through the gastrointestinal tract, is integral for digestive physiology and broader human health. Commensurate with its importance, ENS dysfunction is linked to a range of debilitating gastrointestinal disorders. MicroRNAs (miRNAs), with their pleiotropic roles in post-transcriptional gene regulation, serve as key developmental effectors within the ENS. Herein, we review the regulatory dynamics of miRNAs in ENS ontogeny, showcasing specific miRNAs implicated in both congenital and acquired enteric neuropathies, such as Hirschsprung's disease (HSCR), achalasia, intestinal neuronal dysplasia (IND), chronic intestinal pseudo-obstruction (CIPO), and slow transit constipation (STC). By delineating miRNA-mediated mechanisms in these diseases, we underscore their importance for ENS homeostasis and highlight their potential as therapeutic targets.
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Affiliation(s)
- Amy Marie Holland
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium; Department of Pathology, GROW - Research Institute for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Reindert Jehoul
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Jorunn Vranken
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Stefanie Gabriele Wohl
- Department of Biological and Vision Sciences, College of Optometry, The State University of New York, New York, NY, USA
| | - Werend Boesmans
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium; Department of Pathology, GROW - Research Institute for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands.
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2
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Jin LL, Lu HJ, Shao JK, Wang Y, Lu SP, Huang BF, Hu GN, Jin HC, Wang CQ. Relevance and mechanism of STAT3/miR-221-3p/Fascin-1 axis in EGFR TKI resistance of triple-negative breast cancer. Mol Cell Biochem 2024; 479:3037-3047. [PMID: 38145448 DOI: 10.1007/s11010-023-04907-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 11/25/2023] [Indexed: 12/26/2023]
Abstract
The epidermal growth factor receptor 1 (EGFR) plays a crucial role in the progression of various malignant tumors and is considered a potential target for treating triple-negative breast cancer (TNBC). However, the effectiveness of representative tyrosine kinase inhibitors (TKIs) used in EGFR-targeted therapy is limited in TNBC patients. In our study, we observed that the TNBC cell lines MDA-MB-231 and MDA-MB-468 exhibited resistance to Gefitinib. Treatment with Gefitinib caused an upregulation of Fascin-1 (FSCN1) protein expression and a downregulation of miR-221-3p in these cell lines. However, sensitivity to Gefitinib was significantly improved in both cell lines with either inhibition of FSCN1 expression or overexpression of miR-221-3p. Our luciferase reporter assay confirmed that FSCN1 is a target of miR-221-3p. Moreover, Gefitinib treatment resulted in an upregulation of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in MDA-MB-231 cells. Using Stattic, a small-molecule inhibitor of STAT3, we observed a significant enhancement in the inhibitory effect of Gefitinib on the growth, migration, and invasion of MDA-MB-231 cells. Additionally, Stattic treatment upregulated miR-221-3p expression and downregulated FSCN1 mRNA and protein expression. A strong positive correlation was noted between the expression of STAT3 and FSCN1 in breast cancer tissues. Furthermore, patients with high expression levels of both STAT3 and FSCN1 had a worse prognosis. Our findings suggest that elevated FSCN1 expression is linked to primary resistance to EGFR TKIs in TNBC. Moreover, we propose that STAT3 regulates the expression of miR-221-3p/FSCN1 and therefore modulates resistance to EGFR TKI therapy in TNBC. Combining EGFR TKI therapy with inhibition of FSCN1 or STAT3 may offer a promising new therapeutic option for TNBC.
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Affiliation(s)
- Lu-Lu Jin
- Department of Biomedical Sciences Laboratory, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Hua-Jun Lu
- Department of Oncological Radiotherapy, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Jun-Kang Shao
- Department of Pathology, Affiliated Dongyang Hospital of Wenzhou Medical University, 60 Wu Ning Xi Road, Dongyang, Zhejiang, China
| | - Yan Wang
- Department of Medical Oncology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Shi-Ping Lu
- Department of Pathology, Affiliated Dongyang Hospital of Wenzhou Medical University, 60 Wu Ning Xi Road, Dongyang, Zhejiang, China
| | - Bi-Fei Huang
- Department of Pathology, Affiliated Dongyang Hospital of Wenzhou Medical University, 60 Wu Ning Xi Road, Dongyang, Zhejiang, China
| | - Gui-Nv Hu
- Department of Surgical Oncology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, Zhejiang, China
| | - Hong-Chuan Jin
- Laboratory of Cancer Biology, Key Laboratory of Biotherapy in Zhejiang Province, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, Zhejiang, China
| | - Chao-Qun Wang
- Department of Pathology, Affiliated Dongyang Hospital of Wenzhou Medical University, 60 Wu Ning Xi Road, Dongyang, Zhejiang, China.
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Qu J, Liu S, Li H, Zhou J, Bian Z, Song Z, Jiang Z. Three-layer heterogeneous network based on the integration of CircRNA information for MiRNA-disease association prediction. PeerJ Comput Sci 2024; 10:e2070. [PMID: 38983241 PMCID: PMC11232581 DOI: 10.7717/peerj-cs.2070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 04/29/2024] [Indexed: 07/11/2024]
Abstract
Increasing research has shown that the abnormal expression of microRNA (miRNA) is associated with many complex diseases. However, biological experiments have many limitations in identifying the potential disease-miRNA associations. Therefore, we developed a computational model of Three-Layer Heterogeneous Network based on the Integration of CircRNA information for MiRNA-Disease Association prediction (TLHNICMDA). In the model, a disease-miRNA-circRNA heterogeneous network is built by known disease-miRNA associations, known miRNA-circRNA interactions, disease similarity, miRNA similarity, and circRNA similarity. Then, the potential disease-miRNA associations are identified by an update algorithm based on the global network. Finally, based on global and local leave-one-out cross validation (LOOCV), the values of AUCs in TLHNICMDA are 0.8795 and 0.7774. Moreover, the mean and standard deviation of AUC in 5-fold cross-validations is 0.8777+/-0.0010. Especially, the two types of case studies illustrated the usefulness of TLHNICMDA in predicting disease-miRNA interactions.
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Affiliation(s)
- Jia Qu
- Changzhou University, School of Computer Science and Artificial Intelligence, Changzhou, Jiangsu, China
| | - Shuting Liu
- Changzhou University, School of Computer Science and Artificial Intelligence, Changzhou, Jiangsu, China
| | - Han Li
- Changzhou University, School of Computer Science and Artificial Intelligence, Changzhou, Jiangsu, China
| | - Jie Zhou
- Shaoxing University, School of Computer Science and Engineering, Shaoxing, Zhejiang, China
| | - Zekang Bian
- Jiangnan University, School of AI & Computer Science, Wuxi, Jiangsu, China
| | - Zihao Song
- Changzhou University, School of Computer Science and Artificial Intelligence, Changzhou, Jiangsu, China
| | - Zhibin Jiang
- Shaoxing University, School of Computer Science and Engineering, Shaoxing, Zhejiang, China
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4
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Wang X, Zhou Y, Wang L, Haseeb A, Li H, Zheng X, Guo J, Cheng X, Yin W, Sun N, Sun P, Zhang Z, Yang H, Fan K. Fascin-1 Promotes Cell Metastasis through Epithelial-Mesenchymal Transition in Canine Mammary Tumor Cell Lines. Vet Sci 2024; 11:238. [PMID: 38921985 PMCID: PMC11209228 DOI: 10.3390/vetsci11060238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 05/15/2024] [Accepted: 05/23/2024] [Indexed: 06/27/2024] Open
Abstract
Canine mammary tumors (CMTs) are the most common type of tumor in female dogs. In this study, we obtained a metastatic key protein, Fascin-1, by comparing the proteomics data of in situ tumor and metastatic cell lines from the same individual. However, the role of Fascin-1 in the CMT cell line is still unclear. Firstly, proteomics was used to analyze the differential expression of Fascin-1 between the CMT cell lines CHMm and CHMp. Then, the overexpression (CHMm-OE and CHMp-OE) and knockdown (CHMm-KD and CHMp-KD) cell lines were established by lentivirus transduction. Finally, the differentially expressed proteins (DEPs) in CHMm and CHMm-OE cells were identified through proteomics. The results showed that the CHMm cells isolated from CMT abdominal metastases exhibited minimal expression of Fascin-1. The migration, adhesion, and invasion ability of CHMm-OE and CHMp-OE cells increased, while the migration, adhesion, and invasion ability of CHMm-KD and CHMp-KD cells decreased. The overexpression of Fascin-1 can upregulate the Tetraspanin 4 (TSPAN4) protein in CHMm cells and increase the number of migrations. In conclusion, re-expressed Fascin-1 could promote cell EMT and increase lamellipodia formation, resulting in the enhancement of CHMm cell migration, adhesion, and invasion in vitro. This may be beneficial to improve female dogs' prognosis of CMT.
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Affiliation(s)
- Xin Wang
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Ye Zhou
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Linhao Wang
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Abdul Haseeb
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Hongquan Li
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Xiaozhong Zheng
- Medical Research Council (MRC) Centre for Inflammation Research, Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Jianhua Guo
- Department of Veterinary Pathobiology, Schubot Exotic Bird Health Center, Texas A&M University, College Station, TX 77843, USA
| | - Xiaoliang Cheng
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Wei Yin
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Na Sun
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Panpan Sun
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Zhenbiao Zhang
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Huizhen Yang
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
| | - Kuohai Fan
- Shanxi Key Laboratory for Modernization of TCVM, College of Veterinary Medicine, Shanxi Agricultural University, Jinzhong 030801, China; (X.W.)
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Wei QY, Jin F, Wang ZY, Li BJ, Cao WB, Sun ZY, Mo SJ. MicroRNAs: A novel signature in the metastasis of esophageal squamous cell carcinoma. World J Gastroenterol 2024; 30:1497-1523. [PMID: 38617454 PMCID: PMC11008420 DOI: 10.3748/wjg.v30.i11.1497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/12/2024] [Accepted: 03/01/2024] [Indexed: 03/21/2024] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a malignant epithelial tumor, characterized by squamous cell differentiation, it is the sixth leading cause of cancer-related deaths globally. The increased mortality rate of ESCC patients is predominantly due to the advanced stage of the disease when discovered, coupled with higher risk of metastasis, which is an exceedingly malignant characteristic of cancer, frequently leading to a high mortality rate. Unfortunately, there is currently no specific and effective marker to predict and treat metastasis in ESCC. MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, approximately 22 nucleotides in length. miRNAs are vital in modulating gene expression and serve pivotal regulatory roles in the occurrence, progression, and prognosis of cancer. Here, we have examined the literature to highlight the intimate correlations between miRNAs and ESCC metastasis, and show that ESCC metastasis is predominantly regulated or regulated by genetic and epigenetic factors. This review proposes a potential role for miRNAs as diagnostic and therapeutic biomarkers for metastasis in ESCC metastasis, with the ultimate aim of reducing the mortality rate among patients with ESCC.
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Affiliation(s)
- Qi-Ying Wei
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Feng Jin
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Zhong-Yu Wang
- Department of Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Bing-Jie Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Wen-Bo Cao
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Zhi-Yan Sun
- Division of Special Service, Department of Basic Oncology, School of Basic Medicine, Zhengzhou University, Zhengzhou 450001, Henan Province, China
| | - Sai-Jun Mo
- Department of Basic Science of Oncology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, Henan Province, China
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Jiang Q, Ling GY, Yan J, Tan JY, Nong RB, Li JW, Deng T, Mo LG, Huang QR. Identification of prognostic risk score of disulfidptosis-related genes and molecular subtypes in glioma. Biochem Biophys Rep 2024; 37:101605. [PMID: 38188362 PMCID: PMC10768521 DOI: 10.1016/j.bbrep.2023.101605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 12/05/2023] [Accepted: 12/07/2023] [Indexed: 01/09/2024] Open
Abstract
Background Programmed cell death is closely related to glioma. As a novel kind of cell death, the mechanism of disulfidptosis in glioma remains unclear. Therefore, it is of great importance to study the role of disulfidptosis-related genes (DRGs) in glioma. Methods We first investigated the genetic and transcriptional alterations of 15 DRGs. Two consensus cluster analyses were used to evaluate the association between DRGs and glioma subtypes. In addition, we constructed prognostic DRG risk scores to predict overall survival (OS) in glioma patients. Furthermore, we developed a nomogram to enhance the clinical utility of the DRG risk score. Finally, the expression levels of DRGs were verified by immunohistochemistry (IHC) staining. Results Most DRGs (14/15) were dysregulated in gliomas. The 15 DRGs were rarely mutated in gliomas, and only 50 of 987 samples (5.07 %) showed gene mutations. However, most of them had copy number variation (CNV) deletions or amplifications. Two distinct molecular subtypes were identified by cluster analysis, and DRG alterations were found to be related to the clinical characteristics, prognosis, and tumor immune microenvironment (TIME). The DRG risk score model based on 12 genes was developed and showed good performance in predicting OS. The nomogram confirmed that the risk score had a particularly strong influence on the prognosis of glioma. Furthermore, we discovered that low DRG scores, low tumor mutation burden, and immunosuppression were features of patients with better prognoses. Conclusion The DRG risk model can be used for the evaluation of clinical characteristics, prognosis prediction, and TIME estimation of glioma patients. These DRGs may be potential therapeutic targets in glioma.
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Affiliation(s)
| | | | - Jun Yan
- Department of Neurosurgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Ju-Yuan Tan
- Department of Neurosurgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Ren-Bao Nong
- Department of Neurosurgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jian-Wen Li
- Department of Neurosurgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Teng Deng
- Department of Neurosurgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Li-Gen Mo
- Department of Neurosurgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Qian-Rong Huang
- Department of Neurosurgery, Guangxi Medical University Cancer Hospital, Nanning, China
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7
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Sindhoo A, Sipy S, Khan A, Selvaraj G, Alshammari A, Casida ME, Wei DQ. ESOMIR: a curated database of biomarker genes and miRNAs associated with esophageal cancer. Database (Oxford) 2023; 2023:baad063. [PMID: 37815872 PMCID: PMC10563827 DOI: 10.1093/database/baad063] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/10/2023] [Accepted: 09/16/2023] [Indexed: 10/12/2023]
Abstract
'Esophageal cancer' (EC) is a highly aggressive and deadly complex disease. It comprises two types, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), with Barrett's esophagus (BE) being the only known precursor. Recent research has revealed that microRNAs (miRNAs) play a crucial role in the development, prognosis and treatment of EC and are involved in various human diseases. Biological databases have become essential for cancer research as they provide information on genes, proteins, pathways and their interactions. These databases collect, store and manage large amounts of molecular data, which can be used to identify patterns, predict outcomes and generate hypotheses. However, no comprehensive database exists for EC and miRNA relationships. To address this gap, we developed a dynamic database named 'ESOMIR (miRNA in esophageal cancer) (https://esomir.dqweilab-sjtu.com)', which includes information about targeted genes and miRNAs associated with EC. The database uses analysis and prediction methods, including experimentally endorsed miRNA(s) information. ESOMIR is a user-friendly interface that allows easy access to EC-associated data by searching for miRNAs, target genes, sequences, chromosomal positions and associated signaling pathways. The search modules are designed to provide specific data access to users based on their requirements. Additionally, the database provides information about network interactions, signaling pathways and region information of chromosomes associated with the 3'untranslated region (3'UTR) or 5'UTR and exon sites. Users can also access energy levels of specific miRNAs with targeted genes. A fuzzy term search is included in each module to enhance the ease of use for researchers. ESOMIR can be a valuable tool for researchers and clinicians to gain insight into EC, including identifying biomarkers and treatments for this aggressive tumor. Database URL https://esomir.dqweilab-sjtu.com.
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Affiliation(s)
- Asma Sindhoo
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Dongchuan Road Minhang District, Shanghai 200240, PR China
| | - Saima Sipy
- Sindh Madressatul Islam University, Karachi, Sindh 74600, Pakistan
| | - Abbas Khan
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Dongchuan Road Minhang District, Shanghai 200240, PR China
- State Key Laboratory of Microbial Metabolism, Shanghai–Islamabad–Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai, Minhang 200030, PR China
| | - Gurudeeban Selvaraj
- Centre for Research in Molecular Modelling (CERMM), Department of Chemistry and Biochemistry, Concordia University, Montreal, Quebec H4B 1R6, Canada
| | - Abdulrahman Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mark Earl Casida
- Laboratoire de Spectrom´etrie, Interactions et Chimie th´eorique (SITh), D´epartement de Chimie Mol´eculaire (DCM, UMR CNRS/UGA 5250), Institut de Chimie Mol´eculaire de Grenoble (ICMG, FR2607), Universit´e Grenoble Alpes (UGA), 301 rue de la Chimie BP 53, Grenoble Cedex F-38041, France
| | - Dong-Qing Wei
- Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Dongchuan Road Minhang District, Shanghai 200240, PR China
- State Key Laboratory of Microbial Metabolism, Shanghai–Islamabad–Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Cooperation in Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai, Minhang 200030, PR China
- Peng Cheng Laboratory, Phase I Building 8, Xili Street, Montreal, Vanke Cloud City, Nashan District, Shenzhen, Guangdong 518055, PR China
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8
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Sato H, Hara T, Meng S, Tsuji Y, Arao Y, Sasaki K, Miyoshi N, Kobayashi S, Doki Y, Eguchi H, Ishii H. Drug Discovery and Development of miRNA-Based Nucleotide Drugs for Gastrointestinal Cancer. Biomedicines 2023; 11:2235. [PMID: 37626731 PMCID: PMC10452413 DOI: 10.3390/biomedicines11082235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 07/29/2023] [Accepted: 08/03/2023] [Indexed: 08/27/2023] Open
Abstract
Short non-coding RNAs, miRNAs, play roles in the control of cell growth and differentiation in cancer. Reportedly, the introduction of miRNAs could reduce the biologically malignant behavior of cancer cells, suggesting a possible use as therapeutic reagents. Given that the forced expression of several miRNAs, including miR-302, results in the cellular reprograming of human and mouse cells, which is similar to the effects of the transcription factors Oct4, Sox2, Klf4, and c-Myc, this suggests that the selective introduction of several miRNAs will be able to achieve anti-cancer effects at the epigenetic and metabolic levels. In this review article, we bring together the recent advances made in studies of microRNA-based therapeutic approaches to therapy-resistant cancers, especially in gastrointestinal organs.
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Affiliation(s)
- Hiromichi Sato
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Tomoaki Hara
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
| | - Sikun Meng
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
| | - Yoshiko Tsuji
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
| | - Yasuko Arao
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
| | - Kazuki Sasaki
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Norikatsu Miyoshi
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan
| | - Hideshi Ishii
- Center of Medical Innovation and Translational Research, Department of Medical Data Science, Osaka University Graduate School of Medicine, Yamadaoka 2-2, Suita 565-0871, Osaka, Japan; (H.S.)
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9
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You M, Xie Z, Zhang N, Zhang Y, Xiao D, Liu S, Zhuang W, Li L, Tao Y. Signaling pathways in cancer metabolism: mechanisms and therapeutic targets. Signal Transduct Target Ther 2023; 8:196. [PMID: 37164974 PMCID: PMC10172373 DOI: 10.1038/s41392-023-01442-3] [Citation(s) in RCA: 95] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 03/20/2023] [Accepted: 04/17/2023] [Indexed: 05/12/2023] Open
Abstract
A wide spectrum of metabolites (mainly, the three major nutrients and their derivatives) can be sensed by specific sensors, then trigger a series of signal transduction pathways and affect the expression levels of genes in epigenetics, which is called metabolite sensing. Life body regulates metabolism, immunity, and inflammation by metabolite sensing, coordinating the pathophysiology of the host to achieve balance with the external environment. Metabolic reprogramming in cancers cause different phenotypic characteristics of cancer cell from normal cell, including cell proliferation, migration, invasion, angiogenesis, etc. Metabolic disorders in cancer cells further create a microenvironment including many kinds of oncometabolites that are conducive to the growth of cancer, thus forming a vicious circle. At the same time, exogenous metabolites can also affect the biological behavior of tumors. Here, we discuss the metabolite sensing mechanisms of the three major nutrients and their derivatives, as well as their abnormalities in the development of various cancers, and discuss the potential therapeutic targets based on metabolite-sensing signaling pathways to prevent the progression of cancer.
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Affiliation(s)
- Mengshu You
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Zhuolin Xie
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Nan Zhang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Yixuan Zhang
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China
| | - Desheng Xiao
- Department of Pathology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Shuang Liu
- Department of Oncology, Institute of Medical Sciences, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China
| | - Wei Zhuang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, People's Republic of China.
| | - Lili Li
- Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Ma Liu Shui, Hong Kong.
| | - Yongguang Tao
- Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, 410078, Changsha, Hunan, China.
- NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and School of Basic Medicine, Central South University, 410078, Changsha, Hunan, China.
- Department of Pathology, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, 410078, Changsha, Hunan, China.
- Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Second Xiangya Hospital, Central South University, 410011, Changsha, China.
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10
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Yang JT, Lee IN, Huang C, Huang HC, Wu YP, Chong ZY, Chen JC. ADAM17 Confers Temozolomide Resistance in Human Glioblastoma Cells and miR-145 Regulates Its Expression. Int J Mol Sci 2023; 24:ijms24097703. [PMID: 37175410 PMCID: PMC10178422 DOI: 10.3390/ijms24097703] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 04/13/2023] [Accepted: 04/18/2023] [Indexed: 05/15/2023] Open
Abstract
Glioblastoma (GBM) is a malignant brain tumor, commonly treated with temozolomide (TMZ). Upregulation of A disintegrin and metalloproteinases (ADAMs) is correlated to malignancy; however, whether ADAMs modulate TMZ sensitivity in GBM cells remains unclear. To explore the role of ADAMs in TMZ resistance, we analyzed changes in ADAM expression following TMZ treatment using RNA sequencing and noted that ADAM17 was markedly upregulated. Hence, we established TMZ-resistant cell lines to elucidate the role of ADAM17. Furthermore, we evaluated the impact of ADAM17 knockdown on TMZ sensitivity in vitro and in vivo. Moreover, we predicted microRNAs upstream of ADAM17 and transfected miRNA mimics into cells to verify their effects on TMZ sensitivity. Additionally, the clinical significance of ADAM17 and miRNAs in GBM was analyzed. ADAM17 was upregulated in GBM cells under serum starvation and TMZ treatment and was overexpressed in TMZ-resistant cells. In in vitro and in vivo models, ADAM17 knockdown conferred greater TMZ sensitivity. miR-145 overexpression suppressed ADAM17 and sensitized cells to TMZ. ADAM17 upregulation and miR-145 downregulation in clinical specimens are associated with disease progression and poor prognosis. Thus, miR-145 enhances TMZ sensitivity by inhibiting ADAM17. These findings offer insights into the development of therapeutic approaches to overcome TMZ resistance.
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Affiliation(s)
- Jen-Tsung Yang
- Department of Neurosurgery, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi 61363, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - I-Neng Lee
- Department of Medical Research, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
| | - Cheng Huang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Hsiu-Chen Huang
- Department of Applied Science, National Tsing Hua University South Campus, Hsinchu 30013, Taiwan
- Center for Teacher Education, National Tsing Hua University, Hsinchu 300044, Taiwan
| | - Yu-Ping Wu
- Department of Medical Research, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan
| | - Zhi-Yong Chong
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan
| | - Jui-Chieh Chen
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi 60004, Taiwan
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11
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He XY, Wang XQ, Xiao QL, Liu D, Xu QR, Liu S. Long non-coding RNA NCK1-AS1 functions as a ceRNA to regulate cell viability and invasion in esophageal squamous cell carcinoma via microRNA-133b/ENPEP axis. Cell Cycle 2023; 22:596-609. [PMID: 36412985 PMCID: PMC9928473 DOI: 10.1080/15384101.2022.2138416] [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: 02/07/2021] [Revised: 01/04/2022] [Accepted: 10/17/2022] [Indexed: 11/23/2022] Open
Abstract
This study is designed to explore the role of long non-coding RNAs (lncRNAs) NCK1-AS1 in proliferative and invasive activities of esophageal squamous cell carcinoma (ESCC) cells by binding to microRNA-133b (miR-133b) to regulate ENPEP. Differentially expressed lncRNAs, miRs, genes and their targeting relationships were screened on ESCC-related gene expression datasets GSE17351 and GSE6188. The targeting relationships among NCK1-AS1, miR-133b, and ENPEP were verified using functional assays. Loss- and gain- of function assays were carried out to examine the roles of NCK1-AS1, miR-133b, and ENPEP in ESCC cell proliferative, invasive, migrative and apoptotic abilities as well as tumorigenesis in vivo. Elevated NCK1-AS1 and ENPEP but reduced miR-133b expression were found in ESCC. NCK1-AS1 knockdown or miR-133b overexpression inhibited the malignant properties of ESCC cells as well as tumorigenesis in vivo. NCK1-AS1 regulated the ENPEP expression by competitively binding to miR-133b. ENPEP overexpression reversed inhibition of NCK1-AS1 knockdown on the function of ESCC cells. This study provides evidence that silencing NCK1-AS1 inhibits expression of ENPEP by sponging miR-133b, thereby suppressing ESCC.
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Affiliation(s)
- Xiang-Yuan He
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, P. R. China
| | - Xiu-Qi Wang
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, P. R. China
| | - Qi-Lu Xiao
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, P. R. China
| | - Duan Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, P. R. China
| | - Qi-Rong Xu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, P. R. China
| | - Sheng Liu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, P. R. China
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12
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Ukey S, Jain A, Dwivedi S, Choudhury C, Vishnoi JR, Chugh A, Purohit P, Pareek P, Elhence P, Misra S, Sharma P. Study of MicroRNA (miR-221-3p, miR-133a-3p, and miR-9-5p) Expressions in Oral Submucous Fibrosis and Squamous Cell Carcinoma. Indian J Clin Biochem 2023; 38:73-82. [PMID: 36684498 PMCID: PMC9852399 DOI: 10.1007/s12291-022-01035-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 03/08/2022] [Indexed: 01/25/2023]
Abstract
Oral squamous cell carcinoma (OSCC) is one of the common types of cancer. Its progression follows a transition from oral potentially malignant disorders (OPMDs) such as oral submucous fibrosis (OSMF). Epigenetic modifiers, especially microRNAs (miRNAs), have an appreciable role in the regulation of various carcinogenic pathways which are being used as biomarkers. miRNAs may also be helpful in the differentiation of oral submucous fibrosis from oral squamous cell carcinoma. Three miRNAs, miR-221-3p, miR133a-3p, and miR-9-5p, were found differentially expressed in many cancers in the literature search supported by our preliminary database search-based screening. The literature and our functional enrichment analysis in an earlier study have reported these miRNAs to regulate carcinogenesis at various steps. In the present study, the expression of these miRNAs was examined in 34 histopathologically confirmed OSCC, 30 OSMF, and 29 control (healthy volunteers) human samples. There was a significant downregulation of miRNA-133a-3p in OSCC compared to OSMF and controls, whereas there was up-regulation in oral submucous fibrosis compared to controls. There was no significant difference in the expression of miR-221-3p between OSCC and OSMF, but an upregulation in OSCC compared to controls. miR-9-5p was also found upregulated in both OSCC and OSMF. Further, miR-133a-3p expression was negatively correlated with age, smoking, drinking status, and AJCC staging, whereas miR-9-5p expression was only positively associated with tobacco/ areca nut chewing. The ROC plots, logistic regression model generated, and the correlation between the expression of miR-9-5p and miR-133a-3p in blood and tissue suggests that these could be used as risk stratification biomarkers.
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Affiliation(s)
- Shweta Ukey
- All India Institute of Medical Sciences, Jodhpur, Rajasthan 342005 India
| | - Ankit Jain
- All India Institute of Medical Sciences, Jodhpur, Rajasthan 342005 India
| | | | | | - Jeewan Ram Vishnoi
- All India Institute of Medical Sciences, Jodhpur, Rajasthan 342005 India
| | - Ankita Chugh
- All India Institute of Medical Sciences, Jodhpur, Rajasthan 342005 India
| | - Purvi Purohit
- All India Institute of Medical Sciences, Jodhpur, Rajasthan 342005 India
| | - Puneet Pareek
- All India Institute of Medical Sciences, Jodhpur, Rajasthan 342005 India
| | - Poonam Elhence
- All India Institute of Medical Sciences, Jodhpur, Rajasthan 342005 India
| | - Sanjeev Misra
- All India Institute of Medical Sciences, Jodhpur, Rajasthan 342005 India
| | - Praveen Sharma
- All India Institute of Medical Sciences, Jodhpur, Rajasthan 342005 India
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The LCNetWork: An electronic representation of the mRNA-lncRNA-miRNA regulatory network underlying mechanisms of non-small cell lung cancer in humans, and its explorative analysis. Comput Biol Chem 2022; 101:107781. [DOI: 10.1016/j.compbiolchem.2022.107781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 10/12/2022] [Accepted: 10/19/2022] [Indexed: 11/18/2022]
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14
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Huang Y, Shan G, Yi Y, Liang J, Hu Z, Bi G, Chen Z, Xi J, Ge D, Wang Q, Tan L, Jiang W, Zhan C. FSCN1 induced PTPRF-dependent tumor microenvironment inflammatory reprogramming promotes lung adenocarcinoma progression via regulating macrophagic glycolysis. Cell Oncol (Dordr) 2022; 45:1383-1399. [PMID: 36223033 DOI: 10.1007/s13402-022-00726-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2022] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Macrophages (MΦs) play a dual role in the promotion and suppression of lung adenocarcinoma (LUAD), the function of which is influenced by the metabolic status. The role of protein tyrosine phosphatase receptor type F (PTPRF) in cancer has not been elucidated, and its role in MΦs remains to be seen. METHODS The Seahorse XFe 96 Cell Flow Analyzer detected glucose metabolism in tumor cells and macrophages. The expressions of FSCN1, M-CSF, IL4, PTPRF and IGF1 in macrophages were detected by Western blotting and qRT-PCR. Binding of FSCN1 and IGF1R was detected by co-immunoprecipitation. The tumor status in animals was observed using the IVIS Lumina III imaging system. RESULTS We found that Fascin Actin-Bundling Protein 1 (FSCN1) activates the PI3K-AKT and JAK-STAT signaling pathways in LUAD cells via binding to IGF-1R, thereby promoting the secretion of cytokines such as IL4 and M-CSF. IL4 and M-CSF promote the expression of PTPRF in MΦs, leading to M2 polarization of MΦs by increasing glucose intake and lactate production. In return, M2-type MΦs act on LUAD cells by secreting cytokines such as IGF-1, CCL2, and IL10, which ultimately promote tumor progression. In vivo experiments proved that the knockdown of FSCN1 in A549 cells and PTPRF in MΦs greatly reduced LUAD proliferative and metastatic capacity, which was consistent with the in vitro findings. CONCLUSIONS This study investigated the reprogramming effects of FSCN1 and PTPRF on inflammatory cytokines in the LUAD microenvironment, revealing potential mechanisms by which FSCN1 and PTPRF promote tumor progression and providing a new experimental basis for LUAD treatment.
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Affiliation(s)
- Yiwei Huang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
| | - Guangyao Shan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
| | - Yanjun Yi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
| | - Jiaqi Liang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
| | - Zhengyang Hu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
| | - Guoshu Bi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
| | - Zhencong Chen
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
| | - Junjie Xi
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
| | - Di Ge
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
| | - Qun Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
| | - Lijie Tan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China
| | - Wei Jiang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China.
| | - Cheng Zhan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Shanghai, 200032, China.
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15
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Duca RB, Massillo C, Farré PL, Graña KD, Moro J, Gardner K, Lacunza E, De Siervi A. Hsa-miR-133a-3p, miR-1-3p, GOLPH3 and JUP combination results in a good biomarker to distinguish between prostate cancer and non-prostate cancer patients. Front Oncol 2022; 12:997457. [PMID: 36387263 PMCID: PMC9641240 DOI: 10.3389/fonc.2022.997457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 10/04/2022] [Indexed: 11/02/2023] Open
Abstract
The incidence and mortality of Prostate Cancer (PCa) worldwide correlate with age and bad dietary habits. Previously, we investigated the mRNA/miRNA role on PCa development and progression using high fat diet (HFD) fed mice. Here our main goal was to investigate the effect of HFD on the expression of PCa-related miRNAs and their relevance in PCa patients. We identified 6 up- and 18 down-regulated miRNAs in TRAMP-C1 mice prostate tumors under HFD conditions using miRNA microarrays. Three down-regulated miRNAs: mmu-miR-133a-3p, -1a-3p and -29c-3p were validated in TRAMP-C1 mice prostate tumor by stem-loop RT-qPCR. Hsa-miR-133a-3p/1-3p expression levels were significantly decreased in PCa compared to normal tissues while hsa-miR-133a-3p was found to be further decreased in metastatic prostate cancer tumors compared to non-metastatic PCa. We examined the promoter region of hsa-miR-133a-3p/1-3p genes and compared methylation at these loci with mature miRNA expression. We found that hsa-miR-1-2/miR-133a-1 cluster promoter hypermethylation decreased hsa-miR-133a-3p/1-3p expression in PCa. GOLPH3 and JUP, two hsa-miR-133a-3p and miR-1-3p predicted target genes, were up-regulated in PCa. ROC analysis showed that the combination of hsa-miR-133a-3p, miR-1-3p, GOLPH3 and JUP is a promising panel biomarker to distinguish between PCa and normal adjacent tissue (NAT). These results link PCa aggressiveness to the attenuation of hsa-miR-133a-3p and miR-1-3p expression by promoter hypermethylation. Hsa-miR-133a-3p and miR-1-3p down-regulation may enhance PCa aggressiveness in part by targeting GOLPH3 and JUP.
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Affiliation(s)
- Rocío Belén Duca
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Cintia Massillo
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Paula Lucía Farré
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Karen Daniela Graña
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Juana Moro
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Kevin Gardner
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, United States
| | - Ezequiel Lacunza
- Centro de Investigaciones Inmunológicas Básicas y Aplicadas (CINIBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Buenos Aires, Argentina
| | - Adriana De Siervi
- Laboratorio de Oncología Molecular y Nuevos Blancos Terapéuticos, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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16
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Mbatha S, Hull R, Dlamini Z. Exploiting the Molecular Basis of Oesophageal Cancer for Targeted Therapies and Biomarkers for Drug Response: Guiding Clinical Decision-Making. Biomedicines 2022; 10:biomedicines10102359. [PMID: 36289620 PMCID: PMC9598679 DOI: 10.3390/biomedicines10102359] [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: 07/25/2022] [Revised: 08/24/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
Worldwide, oesophageal cancer is the sixth leading cause of deaths related to cancer and represents a major health concern. Sub-Saharan Africa is one of the regions of the world with the highest incidence and mortality rates for oesophageal cancer and most of the cases of oesophageal cancer in this region are oesophageal squamous cell carcinoma (OSCC). The development and progression of OSCC is characterized by genomic changes which can be utilized as diagnostic or prognostic markers. These include changes in the expression of various genes involved in signaling pathways that regulate pathways that regulate processes that are related to the hallmarks of cancer, changes in the tumor mutational burden, changes in alternate splicing and changes in the expression of non-coding RNAs such as miRNA. These genomic changes give rise to characteristic profiles of altered proteins, transcriptomes, spliceosomes and genomes which can be used in clinical applications to monitor specific disease related parameters. Some of these profiles are characteristic of more aggressive forms of cancer or are indicative of treatment resistance or tumors that will be difficult to treat or require more specialized specific treatments. In Sub-Saharan region of Africa there is a high incidence of viral infections such as HPV and HIV, which are both risk factors for OSCC. The genomic changes that occur due to these infections can serve as diagnostic markers for OSCC related to viral infection. Clinically this is an important distinction as it influences treatment as well as disease progression and treatment monitoring practices. This underlines the importance of the characterization of the molecular landscape of OSCC in order to provide the best treatment, care, diagnosis and screening options for the management of OSCC.
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Affiliation(s)
- Sikhumbuzo Mbatha
- SAMRC Precision Oncology Research Unit (PORU), SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa
- Department of Surgery, Faculty of Health Sciences, Steve Biko Academic Hospital, University of Pretoria, Hatfield 0028, South Africa
- Correspondence: (S.M.); (Z.D.)
| | - Rodney Hull
- SAMRC Precision Oncology Research Unit (PORU), SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa
| | - Zodwa Dlamini
- SAMRC Precision Oncology Research Unit (PORU), SARChI Chair in Precision Oncology and Cancer Prevention (POCP), Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa
- Correspondence: (S.M.); (Z.D.)
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Genetic variants in miR-145 gene are associated with the risk of asthma in Taiwan. Sci Rep 2022; 12:15155. [PMID: 36071121 PMCID: PMC9452491 DOI: 10.1038/s41598-022-18587-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 08/16/2022] [Indexed: 11/29/2022] Open
Abstract
Asthma is a chronic airway inflammation disease and the diagnosis and treatment strategies remain difficult. MicroRNAs play important roles in many biological and pathological processes including asthma development. There is no study confirming the contribution of genetic variants in miR-145 to asthma etiology. We hypothesize that single nucleotide polymorphisms (SNPs) in the promoter region of miR-145 may be associated with the risk of asthma in Taiwanese. We used a case–control study to test this hypothesis. In 198 asthma patients and 453 healthy controls, the genotypes of miR-145 rs4705342 and rs4705343 were determined, and the associations of miR-145 genotypes with asthma risk and severity were evaluated. The distribution of miR-145 rs4705342 genotypes between asthma patients and non-asthmatic control groups were significantly different (p = 0.0187). In multivariable logistic regression analysis, compared with the wild-type TT genotype, individuals carrying the variant genotypes had progressively decreased risks of asthma: the odds ratio (OR) for the heterogeneous variant genotype (CT) and homozygous variant genotype (CC) was 0.77 (95% CI 0.55–1.10, p = 0.1788) and 0.41 (95% CI 0.21–0.79, p = 0.0102), respectively (p for trend = 0.0187). In allelic test, the C allele was associated with a 31% reduced risk of asthma (OR = 0.69, 95% CI 0.53–0.90, p = 0.0070). In addition, the rs4705342 variant genotypes were correlated with the symptom severity (p = 3 × 10–5). Furthermore, the variant genotypes correlated with lower miR-145-5p expression level in serum (p = 0.0001). As for rs4705343, there was no differential distribution of genotypes between cases and controls. Our data provide evidence for miR-145 rs4705342 to serve as a novel biomarker for asthma risk prediction.
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Zhang Z, Wang X, Wang Y, Zhou D, Wu H, Cheng W, Wang Q, Zheng G, Wang J, Gu J. Effect of long noncoding RNA CCAT2 on drug sensitivity to 5-fluorouracil of breast cancer cells through microRNA-145 meditated by p53. J Biochem Mol Toxicol 2022; 36:e23176. [PMID: 35968984 DOI: 10.1002/jbt.23176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 06/02/2022] [Accepted: 07/21/2022] [Indexed: 11/09/2022]
Abstract
The current study was set out to investigate the mechanism by which silenced long noncoding RNA (lncRNA) colon cancer-associated transcript 2 (CCAT2) modulates the cell growth, migration, invasion, and drug sensitivity of breast cancer (BC) cells to 5-fluorouracil (5-Fu) with the involvement of miR-145 and p53. First, high CCAT2 expression was presented in BC cells and tissues. Subsequently, the links between CCAT2 expression and BC clinicopathological features were analyzed. Highly-expressed CCAT2 was linked to lymph node metastasis, positive progesterone receptor, estrogen receptor, and Ki-67 of BC cells. Then, the gain- and loss-of-function approaches were performed to measure the regulatory role of CCAT2 in the biological processes of BC cells. Silencing of CCAT2 suppressed in vitro cell growth, proliferation, invasion, migration abilities, and epithelial-mesenchymal transformation, increased cell apoptosis, and enhanced drug sensitivity of BC cells. Silencing of CCAT2 upregulated miR-145, which was poorly expressed in drug-resistant BC cells. p53 can bind to the miR-145 promoter region and increase miR-145 expression. Upregulation of miR-145 induced by silencing of CCAT2 can be invalidated by p53-siRNA. To conclude, p53-induced activation of miR-145 could be inhibited by CCAT2, while overexpression of CCAT2 could improve the drug resistance of BC cells to 5-Fu.
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Affiliation(s)
- Ziyun Zhang
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Xuedong Wang
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Yueping Wang
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China.,Department of Molecular and Cellular Biology, University of Connecticut, Storrs, Connecticut, USA
| | - Daoping Zhou
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Huaiguo Wu
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Wei Cheng
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Qingping Wang
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Guopei Zheng
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Ji Wang
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China
| | - Juan Gu
- Department of Medical Laboratory Science, Anhui No. 2 Provincial People's Hospital, Hefei, Anhui, China.,Department of Pathology, The Fifth People's Hospital of Wuxi, Nanjing Medical University, Wuxi, Jiangsu, China
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Hofmann L, Medyany V, Ezić J, Lotfi R, Niesler B, Röth R, Engelhardt D, Laban S, Schuler PJ, Hoffmann TK, Brunner C, Jackson EK, Theodoraki MN. Cargo and Functional Profile of Saliva-Derived Exosomes Reveal Biomarkers Specific for Head and Neck Cancer. Front Med (Lausanne) 2022; 9:904295. [PMID: 35899209 PMCID: PMC9309685 DOI: 10.3389/fmed.2022.904295] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 06/20/2022] [Indexed: 12/20/2022] Open
Abstract
Background Exosomes contribute to immunosuppression in head and neck squamous cell carcinoma (HNSCC), a tumor entity which lacks specific tumor biomarkers. Plasma-derived exosomes from HNSCC patients correlate with clinical parameters and have potential as liquid biopsy. Here, we investigate the cargo and functional profile of saliva-derived exosomes from HNSCC patients and their potential as non-invasive biomarkers for disease detection and immunomodulation. Methods Exosomes were isolated from saliva of HNSCC patients (n = 21) and healthy donors (HD, n = 12) by differential ultracentrifugation. Surface values of immune checkpoints and tumor associated antigens on saliva-derived exosomes were analyzed by bead-based flow cytometry using CD63 capture. Upon co-incubation with saliva-derived exosomes, activity and proliferation of T cells were assessed by flow cytometry (CD69 expression, CFSE assay). Adenosine levels were measured by mass spectrometry after incubation of saliva-derived exosomes with exogenous ATP. miRNA profiling of saliva-derived exosomes was performed using the nCounter® SPRINT system. Results Saliva-derived, CD63-captured exosomes from HNSCC patients carried high amounts of CD44v3, PDL1 and CD39. Compared to plasma, saliva was rich in tumor-derived, CD44v3+ exosomes and poor in hematopoietic cell-derived, CD45+ exosomes. CD8+ T cell activity was attenuated by saliva-derived exosomes from HNSCC patients, while proliferation of CD4+ T cells was not affected. Further, saliva-derived exosomes produced high levels of immunosuppressive adenosine. 62 HD- and 31 HNSCC-exclusive miRNAs were identified. Samples were grouped in "Healthy" and "Cancer" based on their saliva-derived exosomal miRNA profile, which was further found to be involved in RAS/MAPK, NF-κB complex, Smad2/3, and IFN-α signaling. Conclusions Saliva-derived exosomes from HNSCC patients were enriched in tumor-derived exosomes whose cargo and functional profile reflected an immunosuppressive TME. Surface values of CD44v3, PDL1 and CD39 on CD63-captured exosomes, adenosine production and the miRNA cargo of saliva-derived exosomes emerged as discriminators of disease and emphasized their potential as liquid biomarkers specific for HNSCC.
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Affiliation(s)
- Linda Hofmann
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Valentin Medyany
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Jasmin Ezić
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Ramin Lotfi
- Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Services Baden-Württemberg-Hessen, Ulm, Germany.,Institute for Transfusion Medicine, University Hospital Ulm, Ulm, Germany
| | - Beate Niesler
- nCounter Core Facility, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
| | - Ralph Röth
- nCounter Core Facility, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
| | - Daphne Engelhardt
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Simon Laban
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Patrick J Schuler
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Thomas K Hoffmann
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Cornelia Brunner
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
| | - Edwin K Jackson
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Marie-Nicole Theodoraki
- Department of Otorhinolaryngology, Head and Neck Surgery, Ulm University Medical Center, Ulm, Germany
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20
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Chen SY, Hsieh JL, Wu PT, Shiau AL, Wu CL. MicroRNA-133 suppresses cell viability and migration of rheumatoid arthritis fibroblast-like synoviocytes by down-regulation of MET, EGFR, and FSCN1 expression. Mol Cell Biochem 2022; 477:2529-2537. [PMID: 35595956 DOI: 10.1007/s11010-022-04457-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/27/2022] [Indexed: 11/25/2022]
Abstract
Aberrant proliferation and migration of fibroblast-like synoviocytes (FLS) are major characteristics of rheumatoid arthritis (RA). MicroRNA-133 (miR-133) is a tumor-suppressive miRNA that targets various genes responsive for cell proliferation and migration. The aim of this study was to examine the effect of miR-133 on RA FLS. A high throughput miRNA microarray was performed in synovium from mice with collagen-induced arthritis (CIA). Expression levels of miR-133 and the putative targets were determined in synovium and FLS from patients with RA and mice with CIA. Overexpression of miR-133 in RA FLS was performed by lentiviral vector-mediated transfer of precursor miRNA (pre-miR). The expression of miR-133a/b was decreased in the joint tissue and FLS of CIA mice, as determined by miRNA array and qRT-PCR. Down-regulation of miR-133a/b expression could also be observed in synovium and FLS from patients with RA. Overexpression of miR-133 reduced cell viability and migration of RA FLS, with decreased levels of FSCN1, EGFR, and MET. Our findings demonstrated the inhibitory effects of miR-133 on FLS viability and migration, and might contribute to the pharmacologic development of miR-133 therapeutics in patients with RA.
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Affiliation(s)
- Shih-Yao Chen
- Department of Nursing, College of Nursing, Chung Hwa University of Medical Technology, 89, Wenhua 1st street, Tainan, 71703, Taiwan.
| | - Jeng-Long Hsieh
- Department of Nursing, College of Nursing, Chung Hwa University of Medical Technology, 89, Wenhua 1st street, Tainan, 71703, Taiwan
| | - Po-Ting Wu
- Department of Orthopaedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Orthopaedics, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
- Medical Device Innovation Center, National Cheng Kung University, Tainan, Taiwan
| | - Ai-Li Shiau
- Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539, Zhongxiao Road, Chiayi, 60002, Taiwan
| | - Chao-Liang Wu
- Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, 539, Zhongxiao Road, Chiayi, 60002, Taiwan.
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
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21
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Ji BY, Pan LR, Zhou JR, You ZH, Peng SL. SMMDA: Predicting miRNA-Disease Associations by Incorporating Multiple Similarity Profiles and a Novel Disease Representation. BIOLOGY 2022; 11:biology11050777. [PMID: 35625505 PMCID: PMC9138858 DOI: 10.3390/biology11050777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/17/2022] [Accepted: 05/17/2022] [Indexed: 12/24/2022]
Abstract
Simple Summary Predicting possible associations between miRNAs and diseases would provide new perspectives on disease diagnosis, pathogenesis, and gene therapy. In this work, considering the limited accessibility, high time consumption and high cost in traditional biological researches, we presented a novel computational method called SMMDA by incorporating multiple similarity profiles and a novel disease rep-resentation to accelerate the identification of potential miRNA-disease associations. SMMDA was intended to be useful for the prediction of associations between miRNAs and diseases, and to be effective for prevention, diagnosis, treatment and prognosis of Human diseases. Abstract Increasing evidence has suggested that microRNAs (miRNAs) are significant in research on human diseases. Predicting possible associations between miRNAs and diseases would provide new perspectives on disease diagnosis, pathogenesis, and gene therapy. However, considering the intrinsic time-consuming and expensive cost of traditional Vitro studies, there is an urgent need for a computational approach that would allow researchers to identify potential associations between miRNAs and diseases for further research. In this paper, we presented a novel computational method called SMMDA to predict potential miRNA-disease associations. In particular, SMMDA first utilized a new disease representation method (MeSHHeading2vec) based on the network embedding algorithm and then fused it with Gaussian interaction profile kernel similarity information of miRNAs and diseases, disease semantic similarity, and miRNA functional similarity. Secondly, SMMDA utilized a deep auto-coder network to transform the original features further to achieve a better feature representation. Finally, the ensemble learning model, XGBoost, was used as the underlying training and prediction method for SMMDA. In the results, SMMDA acquired a mean accuracy of 86.68% with a standard deviation of 0.42% and a mean AUC of 94.07% with a standard deviation of 0.23%, outperforming many previous works. Moreover, we also compared the predictive ability of SMMDA with different classifiers and different feature descriptors. In the case studies of three common Human diseases, the top 50 candidate miRNAs have 47 (esophageal neoplasms), 48 (breast neoplasms), and 48 (colon neoplasms) are successfully verified by two other databases. The experimental results proved that SMMDA has a reliable prediction ability in predicting potential miRNA-disease associations. Therefore, it is anticipated that SMMDA could be an effective tool for biomedical researchers.
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Affiliation(s)
- Bo-Ya Ji
- College of Computer Science and Electronic Engineering, Hunan University, Changsha 410200, China; (B.-Y.J.); (L.-R.P.)
| | - Liang-Rui Pan
- College of Computer Science and Electronic Engineering, Hunan University, Changsha 410200, China; (B.-Y.J.); (L.-R.P.)
| | - Ji-Ren Zhou
- College of Computer Science, Northwestern Polytechnic University, Xi’an 710072, China;
| | - Zhu-Hong You
- College of Computer Science, Northwestern Polytechnic University, Xi’an 710072, China;
- Correspondence: (Z.-H.Y.); (S.-L.P.)
| | - Shao-Liang Peng
- College of Computer Science and Electronic Engineering, Hunan University, Changsha 410200, China; (B.-Y.J.); (L.-R.P.)
- Correspondence: (Z.-H.Y.); (S.-L.P.)
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22
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Cai H, Wang R, Tang Z, Lu T, Cui Y. FSCN1 Promotes Esophageal Carcinoma Progression Through Downregulating PTK6 via its RNA-Binding Protein Effect. Front Pharmacol 2022; 13:868296. [PMID: 35401239 PMCID: PMC8984143 DOI: 10.3389/fphar.2022.868296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/07/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: Esophageal squamous cell carcinoma (ESCC) causes many deaths worldwide every year. Fascin actin-bundling protein 1(FSCN1) has been reported to be a promoter of ESCC via its actin-binding function, however, its new role as an RNA-binding protein (RBP) has not been investigated. Here, we explored the RBP role of FSCN1 in the development of ESCC. Methods: Whole-genome expression sequencing was performed to screen for altered genes after FSCN1 knockdown. RNA immunoprecipitation was performed to determine the target mRNA of FSCN1 as an RBP. In vitro experiments with ECA-109 and KYSE-150 and ex vivo experiments in tumor-bearing mice were performed to investigate the effects of FSCN1 and Protein Tyrosine Kinase 6 (PTK6) on ESCC progression. Results: FSCN1 could downregulate mRNA and the protein level of PTK6. The binding position of PTK6 (PTK6-T2) pre-mRNA to FSCN1 was determined. PTK6-T2 blocked the binding between FSCN1 and the pre-mRNA of PTK6, and thus reversed the promotion effect of FSCN1 on ESCC tumor progression via the AKT/GSK3β signaling pathway. Conclusion: A novel effect of FSCN1, RBP-binding with the pre-mRNA of PTK6, was confirmed to play an important role in ESCC progression. PTK6-T2, which is a specific inhibitor of FSCN1 binding to the pre-mRNA of PTK6, could impede the development of ESCC.
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Affiliation(s)
- Hongfei Cai
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Rui Wang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China.,Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, China
| | - Ze Tang
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Tianyu Lu
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Youbin Cui
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
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23
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Zhang ZD, Wen B, Li DJ, Deng DX, Wu XD, Cheng YW, Liao LD, Long L, Dong G, Xu LY, Li EM. AKT serine/threonine kinase 2-mediated phosphorylation of fascin threonine 403 regulates esophageal cancer progression. Int J Biochem Cell Biol 2022; 145:106188. [PMID: 35219877 DOI: 10.1016/j.biocel.2022.106188] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 02/20/2022] [Accepted: 02/21/2022] [Indexed: 02/05/2023]
Abstract
Fascin is the main actin-bundling protein in filopodia and is highly expressed in metastatic tumor cells. The overexpression of Fascin has been associated with poor clinical prognosis and metastatic progression. Post-translational modifications of Fascin, such as phosphorylation, can affect the proliferation and invasion of tumor cells by regulating the actin-bundling activity of Fascin. However, the phosphorylation sites of Fascin and their corresponding kinases require further exploration. In the current study, we identified novel phosphorylation of Fascin Threonine 403 (Fascin-T403) mediated by AKT serine/threonine kinase 2 (AKT2), which was studied using mass spectrometry data from esophageal cancer tissues (iProX database: IPX0002501000). A molecular dynamics simulation revealed that Fascin-Threonine 403 phosphorylation (Fascin-T403D) had a distinct spatial structure and correlation of amino acid residues, which was different from that of the wild type (Fascin-WT). Low-speed centrifugation assay results showed that Fascin-T403D affected actin cross-linking. To investigate whether Fascin-T403D affected the function of esophageal cancer cells, either Fascin-WT or Fascin-T403D were rescued in Fascin-knockout or siRNA cell lines. We observed that Fascin-T403D could suppress the biological behavior of esophageal cancer cells, including filopodia formation, cell proliferation, and migration. Co-immunoprecipitation (Co-IP) and Duolink in situ proximity ligation assay (PLA) were performed to measure the interaction between Fascin and AKT2. Using in vitro and in vivo kinase assays, we confirmed that AKT2, but not AKT1 or AKT3, is an upstream kinase of Fascin Threonine 403. Taken together, the AKT2-catalyzed phosphorylation of Fascin Threonine 403 suppressed esophageal cancer cell behavior, actin-bundling activity, and filopodia formation.
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Affiliation(s)
- Zhi-Da Zhang
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - Bing Wen
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, China.
| | - Da-Jia Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, China.
| | - Dan-Xia Deng
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, China; Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, China.
| | - Xiao-Dong Wu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, China; Institute of Basic Medical Science, Medical Bioinformatics Center, Shantou University Medical College, Shantou 515041, Guangdong, China.
| | - Yin-Wei Cheng
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, China; Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou 515041, Guangdong, China.
| | - Lian-Di Liao
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, China; Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, China.
| | - Lin Long
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, China; Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, China; Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou 515041, Guangdong, China.
| | - Geng Dong
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, China; Institute of Basic Medical Science, Medical Bioinformatics Center, Shantou University Medical College, Shantou 515041, Guangdong, China.
| | - Li-Yan Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou 515041, Guangdong, China
- Institute of Basic Medical Science, Cancer Research Center, Shantou University Medical College, Shantou 515041, Guangdong, China
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou 515041, Guangdong, China
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24
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Diazzi S, Baeri A, Fassy J, Lecacheur M, Marin-Bejar O, Girard CA, Lefevre L, Lacoux C, Irondelle M, Mounier C, Truchi M, Couralet M, Ohanna M, Carminati A, Berestjuk I, Larbret F, Gilot D, Vassaux G, Marine JC, Deckert M, Mari B, Tartare-Deckert S. Blockade of the pro-fibrotic reaction mediated by the miR-143/-145 cluster enhances the responses to targeted therapy in melanoma. EMBO Mol Med 2022; 14:e15295. [PMID: 35156321 PMCID: PMC8899916 DOI: 10.15252/emmm.202115295] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 01/04/2022] [Accepted: 01/10/2022] [Indexed: 12/20/2022] Open
Abstract
Lineage dedifferentiation toward a mesenchymal‐like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti‐fibrotic drug nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK‐targeted therapy, and delay tumor relapse in a preclinical model of melanoma. Acquisition of this resistant phenotype and its reversion by nintedanib pointed to miR‐143/‐145 pro‐fibrotic cluster as a driver of this mesenchymal‐like phenotype. Upregulation of the miR‐143/‐145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR‐143‐3p and miR‐145‐5p, collaborated to mediate transition toward a drug‐resistant undifferentiated mesenchymal‐like state by targeting Fascin actin‐bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA‐mediated regulatory network that contributes to non‐genetic adaptive drug resistance and provides proof of principle that preventing MAPKi‐induced pro‐fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.
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Affiliation(s)
- Serena Diazzi
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Alberto Baeri
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | - Julien Fassy
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | - Margaux Lecacheur
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Oskar Marin-Bejar
- Laboratory For Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, Leuven, Belgium.,Department of Oncology, KU Leuven, Leuven, Belgium
| | - Christophe A Girard
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Lauren Lefevre
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Caroline Lacoux
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | | | - Carine Mounier
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France.,CYU Université, ERRMECe (EA1391), Neuville-sur-Oise, France
| | - Marin Truchi
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | - Marie Couralet
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | - Mickael Ohanna
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Alexandrine Carminati
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Ilona Berestjuk
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Frederic Larbret
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - David Gilot
- INSERM U1242, University of Rennes, Rennes, France
| | - Georges Vassaux
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France
| | - Jean-Christophe Marine
- Laboratory For Molecular Cancer Biology, VIB Center for Cancer Biology, VIB, Leuven, Belgium.,Department of Oncology, KU Leuven, Leuven, Belgium
| | - Marcel Deckert
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Bernard Mari
- Université Côte d'Azur, CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis, France.,FHU-OncoAge, Nice, France
| | - Sophie Tartare-Deckert
- Université Côte d'Azur, INSERM, C3M, Nice, France.,Equipe labellisée Ligue Contre le Cancer, Nice, France.,FHU-OncoAge, Nice, France
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25
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Guo F, Liu Y, Cheng Y, Zhang Q, Quan W, Wei Y, Hong L. Transcriptome analysis reveals the potential biological function of FSCN1 in HeLa cervical cancer cells. PeerJ 2022; 10:e12909. [PMID: 35178306 PMCID: PMC8817631 DOI: 10.7717/peerj.12909] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 01/19/2022] [Indexed: 01/11/2023] Open
Abstract
Fascin actin-bundling protein 1 (FSCN1), an actin-bundling protein associated with cell migration and invasion, is highly expressed in various tumor tissues. FSCN1 has also been reported to be a marker of increased invasive potential in cervical cancers. However, the functions of FSCN1 are still not fully understood in cervical cancers. Here, the gene expression profile of HeLa cells transfected with FSCN1 shRNA (shFSCN1) was compared with that of cells transfected with empty vector (shCtrl). The results showed that shFSCN1 extensively affected the transcription level of 5,043 genes in HeLa cells. In particular, Gene Ontology (GO) analysis showed that a large number of upregulated genes were annotated with terms including transcription regulation and DNA binding. The downregulated genes were enriched in some cancer pathways, including angiogenesis and cell adhesion. qPCR validation confirmed that FSCN1 knockdown significantly affected the expression of selected genes in HeLa cells either negatively or positively. Expression analysis in TCGA (The Cancer Genome Atlas) revealed that FSCN1 had negative correlations with several transcription factors and a positive correlation with an angiogenic factor (angiopoietin like 4, ANGPTL4) in cervical tumor tissue. In particular, validation by Western blotting showed that FSCN1 knockdown decreased the protein level of ANGPTL4. Our results demonstrated that FSCN1 is not only an actin-binding protein but also a transcriptional regulator and an angiogenic factor in cervical cancer. Thus, our study provides important insights for further study on the regulatory mechanism of FSCN1 in cervical cancer.
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Affiliation(s)
- Fengqin Guo
- Department of Obstetrics & Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Yanliang Liu
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Yanxiang Cheng
- Department of Obstetrics & Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Qifan Zhang
- Department of Obstetrics & Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
| | - Weili Quan
- ABLife BioBigData Institute, Wuhan, Hubei Province, China
| | - Yaxun Wei
- Center for Genome Analysis, ABLife Inc., Wuhan, Hubei Province, China
| | - Li Hong
- Department of Obstetrics & Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China
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26
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Role of MicroRNAs in the Development and Progression of the Four Medulloblastoma Subgroups. Cancers (Basel) 2021; 13:cancers13246323. [PMID: 34944941 PMCID: PMC8699467 DOI: 10.3390/cancers13246323] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 12/21/2022] Open
Abstract
Medulloblastoma is the most frequent malignant brain tumour in children. Medulloblastoma originate during the embryonic stage. They are located in the cerebellum, which is the area of the central nervous system (CNS) responsible for controlling equilibrium and coordination of movements. In 2012, medulloblastoma were divided into four subgroups based on a genome-wide analysis of RNA expression. These subgroups are named Wingless, Sonic Hedgehog, Group 3 and Group 4. Each subgroup has a different cell of origin, prognosis, and response to therapies. Wingless and Sonic Hedgehog medulloblastoma are so named based on the main mutation originating these tumours. Group 3 and Group 4 have generic names because we do not know the key mutation driving these tumours. Gene expression at the post-transcriptional level is regulated by a group of small single-stranded non-coding RNAs. These microRNA (miRNAs or miRs) play a central role in several cellular functions such as cell differentiation and, therefore, any malfunction in this regulatory system leads to a variety of disorders such as cancer. The role of miRNAs in medulloblastoma is still a topic of intense clinical research; previous studies have mostly concentrated on the clinical entity of the single disease rather than in the four molecular subgroups. In this review, we summarize the latest discoveries on miRNAs in the four medulloblastoma subgroups.
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Dashti F, Mirazimi SMA, Rabiei N, Fathazam R, Rabiei N, Piroozmand H, Vosough M, Rahimian N, Hamblin MR, Mirzaei H. The role of non-coding RNAs in chemotherapy for gastrointestinal cancers. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:892-926. [PMID: 34760336 PMCID: PMC8551789 DOI: 10.1016/j.omtn.2021.10.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal (GI) cancers, including colorectal, gastric, hepatic, esophageal, and pancreatic tumors, are responsible for large numbers of deaths around the world. Chemotherapy is the most common approach used to treat advanced GI cancer. However, chemoresistance has emerged as a critical challenge that prevents successful tumor elimination, leading to metastasis and recurrence. Chemoresistance mechanisms are complex, and many factors and pathways are involved. Among these factors, non-coding RNAs (ncRNAs) are critical regulators of GI tumor development and subsequently can induce resistance to chemotherapy. This occurs because ncRNAs can target multiple signaling pathways, affect downstream genes, and modulate proliferation, apoptosis, tumor cell migration, and autophagy. ncRNAs can also induce cancer stem cell features and affect the epithelial-mesenchymal transition. Thus, ncRNAs could possibly act as new targets in chemotherapy combinations to treat GI cancer and to predict treatment response.
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Affiliation(s)
- Fatemeh Dashti
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Mohammad Ali Mirazimi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Nikta Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Fathazam
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negin Rabiei
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Haleh Piroozmand
- Faculty of Veterinary Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
- Radiation Biology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Subha ST, Chin JW, Cheah YK, Mohtarrudin N, Saidi HI. Multiple microRNA signature panel as promising potential for diagnosis and prognosis of head and neck cancer. Mol Biol Rep 2021; 49:1501-1511. [PMID: 34837627 DOI: 10.1007/s11033-021-06954-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Accepted: 11/11/2021] [Indexed: 01/10/2023]
Abstract
MicroRNAs are small non-coding RNA that regulate gene expressions of human body. To date, numerous studies have reported that microRNAs possess great diagnostic and prognostic power in head and neck cancer and had governed a lot of attention. The factor for the successfulness of miRNAs in these aspects is due to cancer being fundamentally tied to genetic changes, which are regulated by these miRNAs. Head and neck cancer, leading the world record for cancer as number sixth, is caused by multiple risk factors such as tobacco consumption, alcohol consumption, dietary factors, ethnicity, family history, and human papilloma virus. It derives at locations such as oral cavity, pharynx, larynx, paranasal sinus and salivary gland and have high rate of mortality with high recurrence rate. Besides, head and neck cancer is also usually having poor prognosis due to its asymptomatic nature. However, this diagnostic and prognostic power can be further improved by using multiple panels of miRNA as a signature or even combined with TNM staging system to obtain even more remarkable results. This is due to multiple factors such as tumour heterogeneity and components of the tumour which may affect the composition of miRNAs. This review covers the examples of such miRNA signatures, compare their diagnostic and prognostic powers, discuss some controversial roles of unreported miRNAs, and the molecular mechanisms of the miRNAs in gene targeting and pathways.
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Affiliation(s)
- Sethu Thakachy Subha
- Department of Otorhinolaryngology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia.
| | - Jun Wei Chin
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Yoke Kqueen Cheah
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Norhafizah Mohtarrudin
- Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, 43400, Serdang, Selangor, Malaysia
| | - Hasni Idayu Saidi
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia
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Zhang Y, Chen R, Deng L, Shuai Z, Chen M. The Effect of Metformin on the Proliferation, Apoptosis and CD133 mRNA Expression of Colon Cancer Stem Cells by Upregulation of miR 342-3p. Drug Des Devel Ther 2021; 15:4633-4647. [PMID: 34815662 PMCID: PMC8602950 DOI: 10.2147/dddt.s336490] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 10/30/2021] [Indexed: 01/01/2023] Open
Abstract
Objective To explore whether metformin (MET) can affect the biological behaviour and CD133 mRNA expression of CD133+ colon cancer stem cells (CCSCs) through miR-342-3p. Methods The direct immunomagnetic bead method was used to select CD133+ CCSCs from the SW480 and HCT116 cell lines, and miRNA-tailing qRT-PCR was used to detect the expression changes of tumor suppressor-related miRNAs (miR-34a, miR-126, miR-143, miR-145, miR-342-3p, miR-342-5p) after MET intervention. Then, miR-342-3p with markedly significant differential expression was selected as the target miRNA. The lentiviruses LV16-hsa-miR-342-3p inhibitor and LV16-NC were used for the transfection inhibition test. CCK-8, flow cytometry, and qRT-PCR were used to detect the cell viability, apoptosis rate, and CD133 mRNA expression of CD133+ CCSCs. Results Under the high-glucose environment, the expression of tumor suppressor-related miRNAs in CCSCs changed differently (p <0.05), MET also had different effects on the expression of tumor suppressor-related miRNA under different glucose concentrations (p<0.05). Among them, MET upregulates the expression of miR-342-3p in CCSCs for the first time. The results of the lentiviruses transfection inhibition test showed that after miR-342-3p was inhibited, the cell viability and apoptosis rate of CD133+ CCSCs did not change significantly compared with before inhibition (p>0.05), but the expression of CD133 mRNA markedly increased (p<0.05). Meanwhile, after MET intervention, the apoptosis rate and the expression of CD133 mRNA of CD133+ CCSCs was significantly increased, and the proliferation of CD133+ CCSCs was obviously inhibited (p<0.05). Conclusion MET upregulating the expression of miR-342-3p may not have a significant effect on the proliferation and apoptosis of CD133+ CCSCs, but it can reduce the expression of CD133 mRNA in CD133+ CCSCs.
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Affiliation(s)
- Yaqin Zhang
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People's Republic of China
| | - Ruofei Chen
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People's Republic of China
| | - Lili Deng
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People's Republic of China
| | - Zongwen Shuai
- Department of Rheumatology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People's Republic of China
| | - Mingwei Chen
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People's Republic of China
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Gupta I, Vranic S, Al-Thawadi H, Al Moustafa AE. Fascin in Gynecological Cancers: An Update of the Literature. Cancers (Basel) 2021; 13:cancers13225760. [PMID: 34830909 PMCID: PMC8616296 DOI: 10.3390/cancers13225760] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/10/2021] [Accepted: 11/12/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Fascin, an actin-binding protein, is upregulated in different types of human cancers. It is reportedly responsible for increasing the invasive and metastatic ability of cancer cells by reducing cell–cell adhesions. This review provides a brief overview of fascin and its interactions with other genes and oncoviruses to induce the onset and progression of cancer. Abstract Fascin is an actin-binding protein that is encoded by the FSCN1 gene (located on chromosome 7). It triggers membrane projections and stimulates cell motility in cancer cells. Fascin overexpression has been described in different types of human cancers in which its expression correlated with tumor growth, migration, invasion, and metastasis. Moreover, overexpression of fascin was found in oncovirus-infected cells, such as human papillomaviruses (HPVs) and Epstein-Barr virus (EBV), disrupting the cell–cell adhesion and enhancing cancer progression. Based on these findings, several studies reported fascin as a potential biomarker and a therapeutic target in various cancers. This review provides a brief overview of the FSCN1 role in various cancers with emphasis on gynecological malignancies. We also discuss fascin interactions with other genes and oncoviruses through which it might induce cancer development and progression.
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Affiliation(s)
- Ishita Gupta
- Department of Basic Medical Science, College of Medicine, QU Health, Qatar University, Doha 2713, Qatar; (I.G.); (S.V.); (H.A.-T.)
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha 2713, Qatar
| | - Semir Vranic
- Department of Basic Medical Science, College of Medicine, QU Health, Qatar University, Doha 2713, Qatar; (I.G.); (S.V.); (H.A.-T.)
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha 2713, Qatar
| | - Hamda Al-Thawadi
- Department of Basic Medical Science, College of Medicine, QU Health, Qatar University, Doha 2713, Qatar; (I.G.); (S.V.); (H.A.-T.)
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha 2713, Qatar
| | - Ala-Eddin Al Moustafa
- Department of Basic Medical Science, College of Medicine, QU Health, Qatar University, Doha 2713, Qatar; (I.G.); (S.V.); (H.A.-T.)
- Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha 2713, Qatar
- Biomedical Research Centre, QU Health, Qatar University, Doha 2713, Qatar
- Correspondence: ; Tel.: +974-4403-7817
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Huang H, Xie L, Feng X, Zheng Z, Ouyang J, Li Y, Yu J. An integrated analysis of DNA promoter methylation, microRNA regulation, and gene expression in gastric adenocarcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1414. [PMID: 34733966 PMCID: PMC8506766 DOI: 10.21037/atm-21-3211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/04/2021] [Indexed: 12/24/2022]
Abstract
Background Gastric adenocarcinoma (GAC), a common type of gastric cancer, poses a significant public health threat worldwide. This study aimed to determine the transcriptional regulatory mechanisms of GAC. Methods HTSeq-FPKM raw data were obtained from The Cancer Genome Atlas Stomach Adenocarcinoma data collection. Subsequently, the limma package in R was used to identify differentially expressed genes (DEGs). Differentially methylated genes (DMGs), DEGs, and differentially expressed microRNAs (miRNAs) in normal, and tumor tissues of the same patients were screened and compared using R software tools. A functional enrichment analysis was performed using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) for various DEGs, DMGs, promoter methylation, and miRNAs. DEG-specific methylation and transcription factors were analyzed using ENCODE ChIP-seq. Results DEGs were centrally modified by the histone trimethylation of lysine 27 on histone H3 (H3K27me3). Upstream transcription factors of DEGs were enriched in different ChIP-seq clusters, such as Forkhead Box M1, E2F Transcription Factor 4, and suppressor of zest 12. Integrated regulatory networks of DEGs, promoter methylation, and miRNAs were constructed. Two miRNAs (hsa-mir-1 and hsa-mir-133a) and four DEGs (A disintegrin and metalloproteinase domain 12, transcription factor AP-2 alpha, solute carrier family 5 member 7, and cadherin 19) separately played important roles in the integrated regulatory network. Therefore, these DEGs, DMGs, promoter methylation, and miRNAs may play an important role in GAC pathogenesis. Conclusions In summary, the present study results provide insights into the oncogenesis and progression of GAC, thus accelerating the development of novel targeted GAC therapies.
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Affiliation(s)
- Hongyun Huang
- Department of General Surgery of Zhujiang Hospital, Southern Medical University, Guangzhou, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Lang Xie
- Department of General Surgery of Zhujiang Hospital, Southern Medical University, Guangzhou, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xiaoxuan Feng
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zheng Zheng
- Department of General Surgery of Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Juntao Ouyang
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yan Li
- Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jinlong Yu
- Department of General Surgery of Zhujiang Hospital, Southern Medical University, Guangzhou, China.,The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
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Fu Z, Wang L, Li S, Chen F, Au-Yeung KKW, Shi C. MicroRNA as an Important Target for Anticancer Drug Development. Front Pharmacol 2021; 12:736323. [PMID: 34512363 PMCID: PMC8425594 DOI: 10.3389/fphar.2021.736323] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer has become the second greatest cause of death worldwide. Although there are several different classes of anticancer drugs that are available in clinic, some tough issues like side-effects and low efficacy still need to dissolve. Therefore, there remains an urgent need to discover and develop more effective anticancer drugs. MicroRNAs (miRNAs) are a class of small endogenous non-coding RNAs that regulate gene expression by inhibiting mRNA translation or reducing the stability of mRNA. An abnormal miRNA expression profile was found to exist widely in cancer cell, which induces limitless replicative potential and evading apoptosis. MiRNAs function as oncogenes (oncomiRs) or tumor suppressors during tumor development and progression. It was shown that regulation of specific miRNA alterations using miRNA mimics or antagomirs can normalize the gene regulatory network and signaling pathways, and reverse the phenotypes in cancer cells. The miRNA hence provides an attractive target for anticancer drug development. In this review, we will summarize the latest publications on the role of miRNA in anticancer therapeutics and briefly describe the relationship between abnormal miRNAs and tumorigenesis. The potential of miRNA-based therapeutics for anticancer treatment has been critically discussed. And the current strategies in designing miRNA targeting therapeutics are described in detail. Finally, the current challenges and future perspectives of miRNA-based therapy are conferred.
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Affiliation(s)
- Zhiwen Fu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Liu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Shijun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Fen Chen
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | | | - Chen Shi
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
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Cui D, Cheung ALM. Roles of microRNAs in tumorigenesis and metastasis of esophageal squamous cell carcinoma. World J Clin Oncol 2021; 12:609-622. [PMID: 34513596 PMCID: PMC8394161 DOI: 10.5306/wjco.v12.i8.609] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 05/11/2021] [Accepted: 07/22/2021] [Indexed: 02/06/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer that is prevalent in Eastern Asia. Despite recent advances in therapy, the outcome of ESCC patients is still dismal. MicroRNAs (miRNAs) are non-coding RNAs which can negatively modulate gene expression at the post-transcriptional level. The involvement and roles of miRNAs have become one of the hot topics of cancer research in recent years. In ESCC, genetic variations within miRNA coding genes were found to have distinct epidemiological significance in different populations. Dysregulated expression of several miRNAs was reported to be associated with therapeutic response. Functionally, miRNAs can act either in an oncogenic or a tumor-suppressive manner during tumorigenesis of ESCC by interrupting signaling pathways associated with cell proliferation, metabolism, cancer stemness, and resistance to chemo- or radiotherapy. Moreover, miRNAs modulate metastasis of ESCC by targeting genes that regulate cytoskeleton dynamics, extracellular matrix remodeling, epithelial-mesenchymal transition, and tumor microenvironment. Most importantly, mounting evidence suggests that inhibiting oncogenic miRNAs or restoring the loss of tumor-suppressive miRNAs has therapeutic potential in the treatment of ESCC. Here, we review and discuss recent studies on the significance, biological functions, and therapeutic potential of miRNAs in tumorigenesis and metastasis of ESCC.
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Affiliation(s)
- Di Cui
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong 999077, China
| | - Annie LM Cheung
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong 999077, China
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Ma Y, Cao X, Shi G, Shi T. MiRNA-145 and Its Direct Downstream Targets in Digestive System Cancers: A Promising Therapeutic Target. Curr Pharm Des 2021; 27:2264-2273. [PMID: 33121400 DOI: 10.2174/1381612826666201029095702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 09/24/2020] [Indexed: 11/22/2022]
Abstract
MicroRNAs (miRNAs) play a vital role in the onset and development of many diseases, including cancers. Emerging evidence shows that numerous miRNAs have the potential to be used as diagnostic biomarkers for cancers, and miRNA-based therapy may be a promising therapy for the treatment of malignant neoplasm. MicroRNA-145 (miR-145) has been considered to play certain roles in various cellular processes, such as proliferation, differentiation and apoptosis, via modulating the expression of direct target genes. Recent reports show that miR-145 participates in the progression of digestive system cancers, and plays crucial and novel roles in cancer treatment. In this review, we summarize the recent knowledge concerning the function of miR-145 and its direct targets in digestive system cancers. We discuss the potential role of miR-145 as a valuable biomarker for digestive system cancers and how miR-145 regulates these digestive system cancers via different targets to explore the potential strategy of targeting miR-145.
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Affiliation(s)
- Yini Ma
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Xiu Cao
- School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
| | - Guojuan Shi
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
| | - Tianlu Shi
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China
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He X, Ma J, Zhang M, Cui J, Yang H. Circ_0007031 enhances tumor progression and promotes 5-fluorouracil resistance in colorectal cancer through regulating miR-133b/ABCC5 axis. Cancer Biomark 2021; 29:531-542. [PMID: 32865180 DOI: 10.3233/cbm-200023] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Colorectal cancer (CRC) remains one of the most commonly diagnosed malignancies worldwide. Circular RNAs (circRNAs) are being found to play crucial roles in human cancer, including CRC. The purpose of this study was to explore the function and mechanism of circ_0007031 on CRC progression and 5-fluorouracil (5-FU) resistance. The levels of circ_0007031, ATP-binding cassette subfamily C member 5 (ABCC5) and miR-133b were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Cell survival and proliferation were detected by the 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Cell colony formation was evaluated using a standard colony formation assay. Transwell assays were performed to determine cell migration and invasion. Targeted correlations among circ_0007031, miR-133b and ABCC5 were verified by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pulldown assays. Animal experiments were performed to observe the role of circ_0007031 in vivo. Our data indicated that circ_0007031 up-regulation was associated with CRC resistance to 5-FU. Circ_0007031 knockdown repressed CRC cell proliferation, migration and invasion and enhanced 5-FU sensitivity. Circ_0007031 directly interacted with miR-133b. Moreover, circ_0007031 knockdown regulated CRC cell progression and 5-FU sensitivity by miR-133b. ABCC5 was a direct target of miR-133b, and circ_0007031 mediated ABCC5 expression via acting as a miR-133b sponge. Furthermore, miR-133b overexpression regulated CRC cell progression and sensitivity to 5-FU by down-regulating ABCC5. Additionally, circ_0007031 knockdown suppressed tumor growth in vivo. Our current work had led to the identification of circ_0007031 knockdown that repressed CRC cell malignant progression and enhanced 5-FU sensitivity via regulating ABCC5 expression by sponging miR-133b.
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Yan Q, Liu L, Yang H, Xu C, Wang Z, Wang Q, Wu Z, Wu C, Dong L, Wang J, Wu M. Long Non-Coding RNA OIP5-AS1 Inhibits the Proliferation and Migration of Esophageal Squamous Carcinoma Cells by Targeting FOXD1/miR-30a-5p Axis and the Effect of Micro- and Nano-Particles on Targeting Transfection System. J Biomed Nanotechnol 2021; 17:1380-1391. [PMID: 34446141 DOI: 10.1166/jbn.2021.3114] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Esophageal cancer is one of the most common human malignancies and ranks sixth for global mortality; the major histological type is esophageal squamous cell carcinoma (ESCC). Here we assessed the effect of long non-coding (lnc) RNA OIP5-AS1 on the miR-30a-5p/Forkhead box protein D1 (FOXD1) axis in ESCC and investigated the underlying mechanism involving the ERK1/2 signaling pathway. lnc RNA OIP5-AS1 was highly expressed in human ESCC tissues and cells, targeted miR-30a-5p, and inhibited miR-30a-5p expression. Additionally, in human ESCC tissues, miR-30a-5p was poorly expressed, whereas FOXD1 mRNA and protein were highly expressed, with a negative correlation between miR-30a-5p and FOXD1 expression. miR-30a-5p targeted and inhibited FOXD1 expression. FOXD1 promoted the proliferation and invasion of ESCC and was related to the ERK1/2 signaling pathway; ERK1/2 inhibitors (LY-3214996) reversed the biological function of FOXD1. miR-30a-5p combined with FOXD1 regulated ERK1/2 expression and inhibited tumor growth in vivo. In this study, micro- and nano-particles were used as carriers to construct Nanocapsules carrying miR-30a-5p mimics and miR-30a-5p inhibitor through self-assembly method, so as to realize an efficient Nanocapsules delivery system of miR-30a-5p to esophageal cancer cells. It provides insights into targeted drug therapy and the development of micro- and nano-particles carriers.
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Affiliation(s)
- Qihang Yan
- Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, PR China
| | - Li Liu
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation, Guangzhou 510000, Guangdong, PR China
| | - Han Yang
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation, Guangzhou 510000, Guangdong, PR China
| | - Chendi Xu
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation, Guangzhou 510000, Guangdong, PR China
| | - Zhen Wang
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation, Guangzhou 510000, Guangdong, PR China
| | - Qi Wang
- Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, PR China
| | - Zixiang Wu
- Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, PR China
| | - Chuanqiang Wu
- Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, PR China
| | - Lingjun Dong
- Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, PR China
| | - Junye Wang
- Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation, Guangzhou 510000, Guangdong, PR China
| | - Ming Wu
- Department of Thoracic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, PR China
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He MQ, Wan JF, Zeng HF, Tang YY, He MQ. miR-133a-5p suppresses gastric cancer through TCF4 down-regulation. J Gastrointest Oncol 2021; 12:1007-1019. [PMID: 34295552 DOI: 10.21037/jgo-20-418] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 05/28/2021] [Indexed: 12/13/2022] Open
Abstract
Background The effect of microRNAs (miRNA) on cancer regulations has received a considerable amount of attention recently. MiR-133a-5p has been identified as an anti-tumor miRNA in several types of cancers. However, the effect of miR-133a-5p on gastric cancer (GC) have not been uncovered. In this study, we sought to evaluate the regulation of TCF4 expression by miR-133-5p and the role of the miR-25-3p/TCF4 axis in the progression of GC, with the aim of identifying a potential therapeutic target for GC. Methods TCGA (The Cancer Genome Atlas), GTEx (The Genotype-Tissue Expression) and GEO (Gene Expression Omnibus) database were used to analyze the expression and prognosis. We performed MTT and EdU assays to elucidate the effect on cell replication. Apoptotic cells were stained with annexin V-fluorescein isothiocyanate and propidium iodide to stain, and then analyzed by flow cytometry. The effect on cell metastasis was investigated in wound healing and transwell assays. A dual-luciferase reporter assay was used to check for the direct targeting of TCF4 by miR-133a-5p. Bioinformatic analysis of the relationship of TCF4 with tumor microenvironment and the signaling cascade of TCF4 was finally performed. Results We found that the level of miR-133a-5p was decreased in both tumor tissues and GC cell lines. MiR-133a-5p inhibited cell growth and metastasis, but promoted cell apoptosis. MiR-133a-5p directly targeted TCF4 and downregulated its expression. TCF4 was highly expressed in tumor and higher level of TCF4 indicated poorer prognosis. Moreover, TCF4 overexpression reversed the aforementioned anti-tumor activity of miR-133a-5p. The expression level of TCF4 was significantly correlated with tumor-infiltrating immune cells. Conclusions Our findings altogether reveal that miR-133a-5p can serve as a tumor suppressor in gastric cancer via the miR-133a-5p/TCF4 pathway.
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Affiliation(s)
- Mu-Qun He
- Department of Medical Oncology, FuJian Medical University Cancer Hospital, FuJian Cancer Hospital, Fuzhou, China
| | - Jian-Feng Wan
- Department of Medical Oncology, FuJian Medical University Cancer Hospital, FuJian Cancer Hospital, Fuzhou, China
| | - Hong-Fu Zeng
- Department of Medical Oncology, FuJian Medical University Cancer Hospital, FuJian Cancer Hospital, Fuzhou, China
| | - Ying-Yan Tang
- Department of Medical Oncology, FuJian Medical University Cancer Hospital, FuJian Cancer Hospital, Fuzhou, China
| | - Mu-Qing He
- Department of Medical Hematology and Oncology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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Ristic B, Kopel J, Sherazi SAA, Gupta S, Sachdeva S, Bansal P, Ali A, Perisetti A, Goyal H. Emerging Role of Fascin-1 in the Pathogenesis, Diagnosis, and Treatment of the Gastrointestinal Cancers. Cancers (Basel) 2021; 13:cancers13112536. [PMID: 34064154 PMCID: PMC8196771 DOI: 10.3390/cancers13112536] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary Gastrointestinal (GI) cancers, including esophageal, gastric, colorectal, liver, and pancreatic cancers, remain as one of the leading causes of death worldwide, with a large proportion accounting for fatalities related to metastatic disease. The active involvement of fascin-1 in forming membrane protrusions crucial for cellular movement has been identified as an important molecular mechanism behind the phenotypic switch from the localized to the metastatic tumor. Thus, fascin-1 expression status in the malignant tissue has been utilized as an important component in determining the patient’s clinicopathological outcomes. In this review, we provide an up-to-date literature review of the role of fascin-1 in the initiation and metastatic progression of GI tract cancers, its involvement in patients’ clinical outcomes, and its potential as a therapeutic target. Abstract Gastrointestinal (GI) cancers, including esophageal, gastric, colorectal, liver, and pancreatic cancers, remain as one of the leading causes of death worldwide, with a large proportion accounting for fatalities related to metastatic disease. Invasion of primary cancer occurs by the actin cytoskeleton remodeling, including the formation of the filopodia, stereocilia, and other finger-like membrane protrusions. The crucial step of actin remodeling in the malignant cells is mediated by the fascin protein family, with fascin-1 being the most active. Fascin-1 is an actin-binding protein that cross-links filamentous actin into tightly packed parallel bundles, giving rise to finger-like cell protrusions, thus equipping the cell with the machinery necessary for adhesion, motility, and invasion. Thus, fascin-1 has been noted to be a key component for determining patient diagnosis and treatment plan. Indeed, the overexpression of fascin-1 in GI tract cancers has been associated with a poor clinical prognosis and metastatic progression. Moreover, fascin-1 has received attention as a potential therapeutic target for metastatic GI tract cancers. In this review, we provide an up-to-date literature review of the role of fascin-1 in the initiation of GI tract cancers, metastatic progression, and patients’ clinical outcomes.
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Affiliation(s)
- Bojana Ristic
- Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA;
| | - Jonathan Kopel
- Department of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA;
| | - Syed A. A. Sherazi
- Department of Medicine, John H Stroger Jr Hospital of Cook County, Chicago, IL 60612, USA;
| | - Shweta Gupta
- Division of Hematology-Oncology, John H Stroger Jr Hospital of Cook County, Chicago, IL 60612, USA;
| | - Sonali Sachdeva
- Department of Cardiology, Boston University School of Medicine, Boston, MA 02118, USA;
| | - Pardeep Bansal
- Department of Gastroenterology, Mercy Health-St. Vincent Medical Center, Toledo, OH 43608, USA;
| | - Aman Ali
- Department of Medicine, The Commonwealth Medical College, Scranton, PA 18510, USA;
| | - Abhilash Perisetti
- Department of Gastroenterology and Hepatology, The University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA;
| | - Hemant Goyal
- The Wright Center for Graduate Medical Education, Scranton, PA 18510, USA
- Correspondence:
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Hoshino I. The usefulness of microRNA in urine and saliva as a biomarker of gastroenterological cancer. Int J Clin Oncol 2021; 26:1431-1440. [PMID: 33835295 DOI: 10.1007/s10147-021-01911-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/24/2021] [Indexed: 12/21/2022]
Abstract
MicroRNA (miR) is a type of short non-coding RNA comprising 21-25 nucleotides. While it has been researched widely, its relationship with cancer was clarified recently and it was found to play a significant role in the development and progression of cancer. Furthermore, miR can remain stable for relatively long periods in the blood by being present in exosomes (extracellular microvesicles) or by forming a complex with the Ago2 protein, which gives rise to cancer-specific miR. It is known that miR can indicate the presence and extent of cancer progression. Several reports have proved that miR in urine and saliva is detected in urinary and oral cancer, respectively, and recent studies have also shown it to be present in cases of gastroenterological cancer, showing evidence of it being a biomarker for cancer. To gather further knowledge on this topic, this review aims to summarize the usefulness of urinary and salivary miR as a biomarker for gastroenterological cancer and discuss its existence, stability mechanism, and direction of future research. The findings will be relevant for physicians and oncologists who routinely treat patients with gastric cancers.
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Affiliation(s)
- Isamu Hoshino
- Division of Gastroenterological Surgery, Chiba Cancer Center, 666-2 Nitonacho, Chuo-ku, Chiba, 260-8717, Japan.
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Bioinformatics-based analysis of the lncRNA-miRNA-mRNA and TF regulatory networks reveals functional genes in esophageal squamous cell carcinoma. Biosci Rep 2021; 40:225786. [PMID: 32662828 PMCID: PMC7441485 DOI: 10.1042/bsr20201727] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/12/2020] [Accepted: 07/13/2020] [Indexed: 02/08/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a 5-year survival rate unsatisfied malignancies. The study aimed to identify the novel diagnostic and prognostic targets for ESCC. Expression profiling (GSE89102, GSE97051, and GSE59973) data were downloaded from the GEO database. Then, differentially expressed (DE) lncRNAs, DEmiRNAs, and genes (DEGs) with P-values < 0.05, and |log2FC| ≥ 2, were identified using GEO2R. Functional enrichment analysis of miRNA-related mRNAs and lncRNA co-expressed mRNA was performed. LncRNA–miRNA–mRNA, protein–protein interaction of miRNA-related mRNAs and DEGs, co-expression, and transcription factors-hub genes network were constructed. The transcriptional data, the diagnostic and prognostic value of hub genes were estimated with ONCOMINE, receiver operating characteristic (ROC) analyses, and Kaplan–Meier plotter, respectively. Also, the expressions of hub genes were assessed through qPCR and Western blot assays. The CDK1, VEGFA, PRDM10, RUNX1, CDK6, HSP90AA1, MYC, EGR1, and SOX2 used as hub genes. And among them, PRDM10, RUNX1, and CDK6 predicted worse overall survival (OS) in ESCC patients. Our results showed that the hub genes were significantly up-regulated in ESCA primary tumor tissues and cell lines, and exhibited excellent diagnostic efficiency. These results suggest that the hub genes may server as potential targets for the diagnosis and treatment of ESCC.
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Liu H, Zhang Y, Li L, Cao J, Guo Y, Wu Y, Gao W. Fascin actin-bundling protein 1 in human cancer: promising biomarker or therapeutic target? Mol Ther Oncolytics 2021; 20:240-264. [PMID: 33614909 PMCID: PMC7873579 DOI: 10.1016/j.omto.2020.12.014] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Fascin actin-bundling protein 1 (FSCN1) is a highly conserved actin-bundling protein that cross links F-actin microfilaments into tight, parallel bundles. Elevated FSCN1 levels have been reported in many types of human cancers and have been correlated with aggressive clinical progression, poor prognosis, and survival outcomes. The overexpression of FSCN1 in cancer cells has been associated with tumor growth, migration, invasion, and metastasis. Currently, FSCN1 is recognized as a candidate biomarker for multiple cancer types and as a potential therapeutic target. The aim of this study was to provide a brief overview of the FSCN1 gene and protein structure and elucidate on its actin-bundling activity and physiological functions. The main focus was on the role of FSCN1 and its upregulatory mechanisms and significance in cancer cells. Up-to-date studies on FSCN1 as a novel biomarker and therapeutic target for human cancers are reviewed. It is shown that FSCN1 is an unusual biomarker and a potential therapeutic target for cancer.
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Affiliation(s)
- Hongliang Liu
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Yu Zhang
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Li Li
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Jimin Cao
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Department of Physiology, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Yujia Guo
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Yongyan Wu
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Department of Biochemistry & Molecular Biology, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
| | - Wei Gao
- Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Shanxi Province Clinical Medical Research Center for Precision Medicine of Head and Neck Cancer, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Department of Otolaryngology Head & Neck Surgery, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Shanxi Medical University, Taiyuan 030001, Shanxi, PR China
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Lin D, Chen X, Tan L. The predictive value of microRNAs for pathological response after neoadjuvant treatment in esophageal squamous cell carcinoma: a systematic review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:420. [PMID: 33842641 PMCID: PMC8033340 DOI: 10.21037/atm-20-3000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Neoadjuvant treatment followed by esophagectomy has been the standard strategy for resectable locally advanced esophageal squamous cell carcinoma (ESCC). Pathological response after neoadjuvant treatment is of vital importance in the determination of long-term survival. Due to the involvement of microRNAs (miRNAs) in ESCC, some studies have proposed miRNA models to predict the pathological response. We aimed to summarize current studies on the predictive value of the miRNA models. We searched the relevant studies on PubMed, Web of Science and Cochrane Library up to February 14, 2020, using the following search term: (esophageal OR esophagus OR oesophageal OR oesophagus) AND (miR OR miRNA OR microRNA) AND (neoadjuvant OR preoperative OR induction). The initial search retrieved 206 studies. We briefly summarized the involvement of miRNAs in the origin, development and chemo- and radioresistance in ESCC. Then, 9 studies were enrolled in the systematic review. A great heterogeneity was observed across these studies. Of the 6 studies with diagnostic tests, the area under curve varied a lot. Although much evidence demonstrated the correlation between miRNAs and pathological response after in ESCC, the current studies has not established any promising models. A well-designed prospective study is essential to investigate the potential predictive models for pathological response after neoadjuvant treatment in ESCC.
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Affiliation(s)
- Dong Lin
- Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Xiaosang Chen
- Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Lijie Tan
- Department of Thoracic Surgery, Zhongshan Hospital of Fudan University, Shanghai, China
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Xin Z, Tong Z, Tan J, Liu C. MicroRNA-145-5p aggravates cell apoptosis and oxidative stress in tongue squamous cell carcinoma. Exp Ther Med 2021; 21:373. [PMID: 33732346 PMCID: PMC7903421 DOI: 10.3892/etm.2021.9804] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 12/08/2020] [Indexed: 12/11/2022] Open
Abstract
MicroRNA-145-5p (miR-145-5p) is expressed in a variety of tumors, but the mechanism underlying miR-145-5p in tongue squamous cell carcinoma (TSCC) is not fully understood. Therefore, the present study investigated the role of miR-145-5p in TSCC. miR-145-5p expression levels in TSCC tissues were analyzed via reverse transcription-quantitative PCR. miR-145-5p mimics and inhibitors were transfected into SCC9 and Cal27 cells. The stability and invasion of SCC9 and Cal27 cells were analyzed by performing Transwell assays, while PI and Annexin V were used to detect cell apoptosis. Oxidative stress levels of superoxide dismutase, malondialdehyde and glutathione peroxidase were measured via ELISA. PI3K/AKT signaling pathway-associated protein expression levels were evaluated using western blotting. miR-145-5p was consistently downregulated in TSCC tissues compared with healthy tissues. miR-145-5p overexpression decreased cell stability and invasion, but promoted cell apoptosis and oxidative stress. In addition, PI3K, AKT and phosphorylated-AKT expression levels were significantly diminished. The results indicated that miR-145-5p overexpression inhibited SCC9 and Cal27 cell stability and invasion, promoted SCC9 and Cal27 cell apoptosis and oxidative stress, and inhibited the PI3K/AKT signaling pathway. The results of the present study suggested that miR-145 may serve as a molecular marker of TSCC.
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Affiliation(s)
- Zengxi Xin
- Department of Prosthodontics, The Second Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Zhou Tong
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Jingyu Tan
- Department of Stomatology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Changfu Liu
- Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
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Xu H, Miao J, Liu S, Liu H, Zhang L, Zhang Q. Long non-coding RNA KCNQ1 overlapping transcript 1 promotes the progression of esophageal squamous cell carcinoma by adsorbing microRNA-133b. Clinics (Sao Paulo) 2021; 76:e2175. [PMID: 33909822 PMCID: PMC8050598 DOI: 10.6061/clinics/2021/e2175] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE The long non-coding RNA (lncRNA) KCNQ1 overlapping transcript 1 (KCNQ1OT1) exerts vital regulatory functions in diverse tumors. However, the biological function of KCNQ1OT1 in esophageal squamous cell carcinoma (ESCC) remains unclear. METHODS KCNQ1OT1 expression was detected in ESCC tissues using quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, apoptosis, migration, and invasion were detected by the CCK-8 assay, EdU assay, flow cytometry analysis, and Transwell experiments, respectively. Bioinformatics analysis, luciferase reporter experiments, and RNA immunoprecipitation assays were used to predict and validate the regulatory relationships between KCNQ1OT1, microRNA-133b (miR-133b) and epidermal growth factor receptor (EGFR). RESULTS KCNQ1OT1 expression was remarkably upregulated in ESCC tissues and cell lines. Overexpression of KCNQ1OT1 markedly promoted ESCC cell proliferation, migration, and invasion and enhanced the expression of N-cadherin, MMP-2, and MMP-9, but inhibited apoptosis and E-cadherin expression in ESCC cell lines; KCNQ1OT1 knockdown exerted the opposite effects. KCNQ1OT1 could directly bind to miR-133b and suppress its expression, and miR-133b reversed the effects of KCNQ1OT1 overexpression in ESCC cells. MiR-133b reduced the expression of epidermal growth factor receptor (EGFR); further, KCNQ1OT1 activated the phosphatidylinositol 3-kinase/AKT serine/threonine kinase 1 (PI3K/AKT) signaling pathway by repressing miR-133b repression and indirectly upregulating EGFR. KCNQ1OT1 expression was positively correlated with EGFR mRNA expression and negatively correlated with miR-133b expression. CONCLUSION KCNQ1OT1 facilitates ESCC progression by sponging miR-133b and activating the EGFR/PI3K/AKT pathway.
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Affiliation(s)
- Haitao Xu
- Department of Thoracic Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Jing Miao
- Department of Pediatrics, Binzhou People’s Hospital, Binzhou, Shandong 256603, China
| | - Shuai Liu
- Department of Thoracic Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Hongjian Liu
- Department of Thoracic Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Lianguo Zhang
- Department of Thoracic Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
| | - Qingguang Zhang
- Department of Thoracic Surgery, Binzhou Medical University Hospital, Binzhou, Shandong 256603, China
- *Corresponding author. E-mail:
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Grzywa TM, Klicka K, Włodarski PK. Regulators at Every Step-How microRNAs Drive Tumor Cell Invasiveness and Metastasis. Cancers (Basel) 2020; 12:E3709. [PMID: 33321819 PMCID: PMC7763175 DOI: 10.3390/cancers12123709] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/03/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Tumor cell invasiveness and metastasis are the main causes of mortality in cancer. Tumor progression is composed of many steps, including primary tumor growth, local invasion, intravasation, survival in the circulation, pre-metastatic niche formation, and metastasis. All these steps are strictly controlled by microRNAs (miRNAs), small non-coding RNA that regulate gene expression at the post-transcriptional level. miRNAs can act as oncomiRs that promote tumor cell invasion and metastasis or as tumor suppressor miRNAs that inhibit tumor progression. These miRNAs regulate the actin cytoskeleton, the expression of extracellular matrix (ECM) receptors including integrins and ECM-remodeling enzymes comprising matrix metalloproteinases (MMPs), and regulate epithelial-mesenchymal transition (EMT), hence modulating cell migration and invasiveness. Moreover, miRNAs regulate angiogenesis, the formation of a pre-metastatic niche, and metastasis. Thus, miRNAs are biomarkers of metastases as well as promising targets of therapy. In this review, we comprehensively describe the role of various miRNAs in tumor cell migration, invasion, and metastasis.
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Affiliation(s)
- Tomasz M. Grzywa
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Klaudia Klicka
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Paweł K. Włodarski
- Department of Methodology, Medical University of Warsaw, 02-091 Warsaw, Poland; (T.M.G.); (K.K.)
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Lamb MC, Tootle TL. Fascin in Cell Migration: More Than an Actin Bundling Protein. BIOLOGY 2020; 9:biology9110403. [PMID: 33212856 PMCID: PMC7698196 DOI: 10.3390/biology9110403] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 11/12/2020] [Accepted: 11/13/2020] [Indexed: 12/14/2022]
Abstract
Simple Summary Cell migration is an essential biological process that regulates both development and diseases, such as cancer metastasis. Therefore, understanding the factors that promote cell migration is crucial. One of the factors known to regulate cell migration is the actin-binding protein, Fascin. Fascin is typically thought to promote cell migration through bundling actin to form migratory structures such as filopodia and invadapodia. However, Fascin has many other functions in the cell that may contribute to cell migration. How these novel functions promote cell migration and are regulated is still not well understood. Here, we review the structure of Fascin, the many functions of Fascin and how they may promote cell migration, how Fascin is regulated, and Fascin’s role in diseases such as cancer metastasis. Abstract Fascin, an actin-binding protein, regulates many developmental migrations and contributes to cancer metastasis. Specifically, Fascin promotes cell motility, invasion, and adhesion by forming filopodia and invadopodia through its canonical actin bundling function. In addition to bundling actin, Fascin has non-canonical roles in the cell that are thought to promote cell migration. These non-canonical functions include regulating the activity of other actin-binding proteins, binding to and regulating microtubules, mediating mechanotransduction to the nucleus via interaction with the Linker of the Nucleoskeleton and Cytoskeleton (LINC) Complex, and localizing to the nucleus to regulate nuclear actin, the nucleolus, and chromatin modifications. The many functions of Fascin must be coordinately regulated to control cell migration. While much remains to be learned about such mechanisms, Fascin is regulated by post-translational modifications, prostaglandin signaling, protein–protein interactions, and transcriptional means. Here, we review the structure of Fascin, the various functions of Fascin and how they contribute to cell migration, the mechanisms regulating Fascin, and how Fascin contributes to diseases, specifically cancer metastasis.
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Uddin MN, Wang X. The landscape of long non-coding RNAs in tumor stroma. Life Sci 2020; 264:118725. [PMID: 33166593 DOI: 10.1016/j.lfs.2020.118725] [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: 07/18/2020] [Revised: 10/26/2020] [Accepted: 11/03/2020] [Indexed: 02/06/2023]
Abstract
AIMS Long non-coding RNAs (lncRNAs) are associated with cancer development, while their relationship with the cancer-associated stromal components remains poorly understood. In this review, we performed a broad description of the functional landscape of stroma-associated lncRNAs in various cancers and their roles in regulating the tumor-stroma crosstalk. MATERIALS AND METHODS We carried out a systematic literature review of PubMed, Scopus, Medline, Bentham, and EMBASE (Elsevier) databases by using the keywords "LncRNAs in cancer," "LncRNAs in tumor stroma," "stroma," "cancer-associated stroma," "stroma in the tumor microenvironment," "tumor-stroma crosstalk," "drug resistance of stroma," and "stroma in immunosuppression" till July 2020. We collected the latest articles addressing the biological functions of stroma-associated lncRNAs in cancer. KEY FINDINGS These articles reported that dysregulated stroma-associated lncRNAs play significant roles in modulating the tumor microenvironment (TME) by the regulation of tumor-stroma crosstalk, epithelial to mesenchymal transition (EMT), endothelial to mesenchymal transition (EndMT), extracellular matrix (ECM) turnover, and tumor immunity. SIGNIFICANCE The tumor stroma is a substantial portion of the TME, and the dysregulation of tumor stroma-associated lncRNAs significantly contributes to cancer initiation, progression, angiogenesis, immune evasion, metastasis, and drug resistance. Thus, stroma-associated lncRNAs could be potentially useful targets for cancer therapy.
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Affiliation(s)
- Md Nazim Uddin
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China; Institute of Food Science and Technology, Bangladesh Council of Scientific and Industrial Research (BCSIR), Dhaka 1205, Bangladesh
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China.
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Jia H, Wang H, Xia F, Sun Y, Liu H, Yan L, Li S, Jiang D, Xu M. MiR-624-3p Promotes Esophageal Squamous Cell Carcinoma Progression via Targeting Phosphatase and Tensin Homologue. DNA Cell Biol 2020; 39:2257-2264. [PMID: 33147068 DOI: 10.1089/dna.2020.6101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The emerging role of miRNA as regulators in esophageal squamous cell carcinoma (ESCC) progression has aroused great attention recently. In this study, the effects of miR-624-3p in ESCC progression were explored through cell proliferation, colony formation, cell cycle, and apoptosis analyses. Results showed that increased expression of miR-624-3p enhanced cancer cell viability, proliferation, migration, and invasion but inhibited apoptosis in ESCC. Moreover, luciferase reporter assay demonstrated that miR-624-3p bound to the 3'-untranslated region of phosphatase and tensin homologue (PTEN). Further study showed that miR-624-3p exerted its tumor promoting role through targeting PTEN. Taken together, these results elucidate the regulatory role of miR-624-3p in ESCC progression, shedding light on its possible clinical application in ESCC treatment.
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Affiliation(s)
- Hongyu Jia
- Department of Digestive Internal Medicine, First Hospital of Qinhuangdao, Hebei, P.R. China
| | - Henan Wang
- Department of Digestive Internal Medicine, First Hospital of Qinhuangdao, Hebei, P.R. China
| | - Fengyu Xia
- Department of Digestive Internal Medicine, First Hospital of Qinhuangdao, Hebei, P.R. China
| | - Yan Sun
- Department of Digestive Internal Medicine, First Hospital of Qinhuangdao, Hebei, P.R. China
| | - Hongli Liu
- Department of Digestive Internal Medicine, First Hospital of Qinhuangdao, Hebei, P.R. China
| | - Lili Yan
- Department of Digestive Internal Medicine, First Hospital of Qinhuangdao, Hebei, P.R. China
| | - Shanshan Li
- Department of Digestive Internal Medicine, First Hospital of Qinhuangdao, Hebei, P.R. China
| | - Dongchun Jiang
- Department of Digestive Internal Medicine, First Hospital of Qinhuangdao, Hebei, P.R. China
| | - Meimei Xu
- Department of Digestive Internal Medicine, First Hospital of Qinhuangdao, Hebei, P.R. China
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Zheng Y, Luo M, Lü M, Zhou T, Liu F, Guo X, Zhang J, Kang M. Let-7c-5p Inhibits Cell Proliferation and Migration and Promotes Apoptosis via the CTHRC1/AKT/ERK Pathway in Esophageal Squamous Cell Carcinoma. Onco Targets Ther 2020; 13:11193-11209. [PMID: 33173311 PMCID: PMC7646436 DOI: 10.2147/ott.s274092] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 10/14/2020] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Let-7c-5p has been identified as a tumor suppressor in various malignancies; however, its function and mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we explored the role and potential molecular mechanism of let-7c-5p in ESCC. MATERIALS AND METHODS mRNA and protein expression levels were detected by quantitative real time-polymerase chain reaction (qRT-PCR) and Western blotting. The cell counting kit-8 (CCK-8) assay was used to assess cell proliferation. Flow cytometry analysis was used to detect cell apoptosis, and cell migration was measured by wound healing assay and Transwell assays. The dual-luciferase reporter assay was used to verify the targeting relationship between let-7c-5p and CTHRC1. The tumor xenograft model was constructed to further verify the effect of let-7c-5p on the growth of ESCC in vivo. RESULTS We found that let-7c-5p expression was downregulated in ESCC tissue and cell lines, and its reduced expression was correlated with TNM staging and lymph node metastasis. Next, we found that let-7c-5p can be used to discriminate ESCC patients from normal control subjects by receiver operating characteristic (ROC) curve analysis. Subsequently, we observed that let-7c-5p overexpression inhibited proliferation and migration and promoted apoptosis, while let-7c-5p down-regulation promoted proliferation and migration and inhibited apoptosis of TE-1 and KYSE150 cells. Furthermore, let-7c-5p overexpression inhibited tumor growth, while let-7c-5p inhibition promoted tumor growth in xenograft models. In addition, we confirmed that CTHRC1 was a direct target gene of let-7c-5p. Then, we found that let-7c-5p level was negatively correlated with CTHRC1 and negatively regulated expression of CTHRC1 in ESCC. Moreover, we confirmed that let-7c-5p upregulation significantly reduced the phosphorylation of AKT and ERK by directly inhibiting CTHRC1, while let-7c-5p downregulation showed the opposite effect. CONCLUSION Our findings indicate that let-7c-5p is markedly downregulated in ESCC and suppresses proliferation and migration and promotes apoptosis of ESCC cells by inhibiting the AKT and ERK signaling pathways through negatively regulating CTHRC1. Therefore, these results suggest that let-7c-5p may represent a novel biomarker and therapeutic target for ESCC.
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Affiliation(s)
- Yaxin Zheng
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, People’s Republic of China
| | - Mao Luo
- Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Drug Discovery Research Center, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
| | - Muhan Lü
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, People’s Republic of China
| | - Tiejun Zhou
- Department of Pathology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichaun, People’s Republic of China
| | - Fang Liu
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, People’s Republic of China
| | - Xiaoni Guo
- School of Public Health and Management, Chongqing Medical University, Chongqing, People’s Republic of China
| | - Jian Zhang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, People’s Republic of China
| | - Min Kang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China
- Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, People’s Republic of China
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Li Z, Liu J, Chen H, Zhang Y, Shi H, Huang L, Tao J, Shen R, Wang T. Ferritin Light Chain (FTL) competes with long noncoding RNA Linc00467 for miR-133b binding site to regulate chemoresistance and metastasis of colorectal cancer. Carcinogenesis 2020; 41:467-477. [PMID: 31675755 DOI: 10.1093/carcin/bgz181] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 10/18/2019] [Accepted: 10/25/2019] [Indexed: 12/22/2022] Open
Abstract
Although the colorectal cancer (CRC) mortality rates are decreasing in virtue of CRC screening and improved therapeutic methods, CRC is still a leading cause of cancer deaths. One of the main causes is chemoresistance occurrence in CRC. Understanding of the molecular mechanisms of chemoresistance benefits to CRC diagnosis and treatment. In this study, gene expression was determined by western blot and qRT-PCR. The biological functions of genes in CRC cells were studied by knocking down or overexpressing the gene in CRC cells and then analyzing cell sensitivity to 5-Fu by the MTT assay and the flow cytometry, and analyzing cell migration and invasion by transwell assays. The luciferase reporter assay was used to examine microRNA regulation of target gene expression, and biotin pull-down assay was performed to detect interaction between RNA molecules. This study found that ferritin light chain (FTL) and long intergenic noncoding RNA Linc00467 were both upregulated in CRC tissues and cell lines, and inversely correlated to CRC patient survival. FTL and Linc00467 promoted CRC cells abilities to resistance against 5-fluor-ouracil (5-Fu), migration and invasion. These effects were compromised by miR-133b which targeted both FTL and Linc00467. miR-133b interacted with Linc00467 and miR-133b inhibitor prevented Linc00467 knockdown-induced alternations of FTL expression and biological functions. Both FTL and Linc00467 are oncogenes in CRC. FTL expression upregulated in CRC via Linc00467/ miR-133b axis, and leads to CRC cell resistance against 5-FU treatment and promotes CRC metastasis. FTL expression upregulated in CRC via Linc00467/miR-133b axis, and leads to CRC cell resistance to 5-FU treatment and promotes CRC metastasis.
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Affiliation(s)
- Zengyao Li
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jing Liu
- Department of Respiratory, Wuxi People's Hospital, Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Hang Chen
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Ye Zhang
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haoze Shi
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Longchang Huang
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jianxin Tao
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Renhui Shen
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tong Wang
- Department of General Surgery, and , Wuxi, Jiangsu.,Nanjing Medical University, Nanjing, Jiangsu, China
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