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Hu S, Ye J, Wang K, Xiong Y, Nie X. Inhibition of miR-9 Combined With Cisplatin Targeting APE1 Against Angiogenesis in Osteosarcoma. J Craniofac Surg 2024; 35:2189-2193. [PMID: 38771203 DOI: 10.1097/scs.0000000000010325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 04/13/2024] [Indexed: 05/22/2024] Open
Abstract
Osteosarcoma (OS) is a highly malignant tumor, and chemotherapy resistance suggests poor prognosis in OS patients. In this study, the authors discovered that miR-9 has a pro-angiogenic role in OS. The anti-angiogenic effects of cisplatin were greatly increased when miR-9 was suppressed in OS. In addition, the authors demonstrated that miR-9 plays a pro-angiogenic role by targeting apoptosis-inducing factor 1 (APE1) in OS. Importantly, our in vivo experiments showed that inhibition of miR-9 combined with cisplatin could suppress xenograft tumor growth by targeting APE1 and decreasing angiogenesis in OS. In summary, our results suggest that miR-9 plays a role as a tumor promoter, and inhibiting miR-9 and APE1 is a new strategy for inhibiting OS angiogenesis and chemotherapy resistance.
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Affiliation(s)
- Sunqiang Hu
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
| | - Jiaqi Ye
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
| | - Keyu Wang
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
| | - Yan Xiong
- Department of Orthopaedics, Daping Hospital, Army Medical University, Chongqing, China
| | - Xin Nie
- Department of Oral and Maxillofacial Surgery, School & Hospital of Stomatology, Wenzhou Medical University, Wenzhou
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2
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Jurj A, Fontana B, Varani G, Calin GA. Small molecules targeting microRNAs: new opportunities and challenges in precision cancer therapy. Trends Cancer 2024; 10:809-824. [PMID: 39107162 PMCID: PMC11961049 DOI: 10.1016/j.trecan.2024.06.006] [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: 11/27/2023] [Revised: 06/17/2024] [Accepted: 06/20/2024] [Indexed: 08/09/2024]
Abstract
Noncoding RNAs, especially miRNAs, play a pivotal role in cancer initiation and metastasis, underscoring their susceptibility to precise modulation via small molecule inhibitors. This review examines the innovative strategy of targeting oncogenic miRNAs with small drug-like molecules, an approach that can reshape the cancer treatment landscape. We review the current understanding of the multifaceted roles of miRNAs in oncogenesis, highlighting emerging therapeutic paradigms that have the potential to expand cancer treatment options. As research on small molecule inhibitors of miRNA is still in its early stages, ongoing investigative efforts and the development of new technologies and chemical matter are essential to fulfill the significant potential of this innovative approach to cancer treatment.
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Affiliation(s)
- Ancuta Jurj
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Beatrice Fontana
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Gabriele Varani
- Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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3
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Bi S, He H, Gao F, Zhao Y. Ultrasensitive Photoelectrochemical Biosensor for Dual-miRNAs Detection Based on Molecular Logic Gates and Methylene Blue Sensitized ZnO@CdS@Au Nanorods. ACS APPLIED MATERIALS & INTERFACES 2024; 16:36194-36203. [PMID: 38952261 DOI: 10.1021/acsami.4c08276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/03/2024]
Abstract
The occurrence of cancer is often closely related to multiple tumor markers, so it is important to develop multitarget detection methods. By the proper design of the input signals and logical operations of DNA logic gates, detection and diagnosis of cancer at different stages can be achieved. For example, in the early stages, specific input signals can be designed to correspond to early specific tumor markers, thereby achieving early cancer detection. In the late stage, logic gates for multitarget detection can be designed to simultaneously detect multiple biomarkers to improve diagnostic accuracy and comprehensiveness. In this work, we constructed a dual-target-triggered DNA logic gate for anchoring DNA tetrahedra, where methylene blue was embedded in the DNA tetrahedra to sensitize ZnO@CdS@Au, achieving ultrasensitive detection of the target substance. We tested the response of AND and OR logic gates to the platform. For AND logic gates, the sensing platform only responds when both miRNAs are present. In the concentration range of 10 aM to 10 nM, the photoelectric signal gradually increases with an increase of the target concentration. Subsequently, we used OR logic gates for miRNA detection. Even if only one target exists, the sensing platform exhibits excellent performance. Similarly, within the concentration range of 10 aM to 10 nM, the photoelectric signal gradually increases with an increase of the target concentration. The minimum detection limit is 1.10 aM. Whether it is the need to detect multiple targets simultaneously or only one of them, we can achieve it by selecting the appropriate logic gate. This strategy holds promising application prospects in fields such as biosensing, medical diagnosis, and environmental monitoring.
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Affiliation(s)
- Shiliang Bi
- Hebei Key Laboratory of Nano-Biotechnology, College of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao 066004, China
| | - Hanxiao He
- Hebei Key Laboratory of Nano-Biotechnology, College of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao 066004, China
| | - Faming Gao
- Hebei Key Laboratory of Nano-Biotechnology, College of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao 066004, China
| | - Yang Zhao
- Hebei Key Laboratory of Nano-Biotechnology, College of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao 066004, China
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4
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Li C, Wang M, Li PF, Sheng J, Fu Q. Construction of Smart DNA-Based Drug Delivery Systems for Cancer Therapy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2306257. [PMID: 38377302 DOI: 10.1002/smll.202306257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 02/10/2024] [Indexed: 02/22/2024]
Abstract
Due to the disadvantages of poor targeting, slow action, and low effectiveness of current commonly used cancer treatments, including surgery, chemotherapy, and radiotherapy, researchers have turned to DNA as a biomaterial for constructing drug delivery nanocarriers. DNA is favored for its biocompatibility and programmability. In order to overcome the limitations associated with traditional drug delivery systems (DDSs), researchers have developed smart-responsive DNA DDSs that can control drug release in response to specific physical or chemical stimuli at targeted sites. In this review, a summary of multiple targeted ligand structures is provided, various shapes of stable DNA nanomaterials, and different stimuli-responsive drug release strategies in DNA DDSs. Specifically, targeted cell recognition, in vivo stable transport, and controlled drug release of smart DDSs are focused. Finally, the further development prospects and challenges of clinical application of DNA nanomaterials in the field of smart drug delivery are discussed. The objective of this review is to enhance researchers' comprehension regarding the potential application of DNA nanomaterials in precision drug delivery, with the aim of expediting the clinical implementation of intelligent DDSs.
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Affiliation(s)
- Congcong Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Mengzhen Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Pei-Feng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
| | - Junyue Sheng
- Qingdao No.58 High School of Shandong Province, 20 Jiushui Road, Qingdao, 266100, China
| | - Qinrui Fu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, 266021, China
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5
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Salehi A. A novel therapeutic strategy: the significance of exosomal miRNAs in acute myeloid leukemia. Med Oncol 2024; 41:62. [PMID: 38253748 DOI: 10.1007/s12032-023-02286-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 12/12/2023] [Indexed: 01/24/2024]
Abstract
Acute myeloid leukemia (AML) is a fast-growing blood cancer that interferes with the normal growth of blood cells in the bone marrow and blood. It is characterized by its unpredictable outlook and high death rate. The main treatment for AML is chemotherapy, but this often results in drug resistance and the possibility of the disease returning. For this reason, new biomarkers are necessary to diagnose, predict, and treat this disease. Research has demonstrated that cells responsible for AML release exosomes that interact with the disease's microenvironment. These exosomes have significant roles in promoting leukemia growth, suppressing normal hematopoiesis, facilitating angiogenesis, and contributing to drug resistance in AML. Further investigations have shown that these exosomes contain miRNAs, which are transferred to target cells and have functional roles. Biomarkers are utilized to assess various aspects of tumor cell behavior, including proliferation, apoptosis, angiogenesis, changes in the microenvironment, transfer of drug resistance, and stability in serum and blood plasma. In this research, we showed that exosomal miRNAs and exosomes have the potential to be used as indicators for detecting various phases of AML and can aid in its medical treatment. Furthermore, they can be specifically targeted for therapeutic purposes in addressing this condition.
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Affiliation(s)
- Ali Salehi
- Department of Cellular and Molecular Biology, Faculty of New Science and Technology, Tehran Medical Branch, Islamic Azad University, Tehran, Iran.
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6
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Ding T, Li W, Li F, Ren M, Wang W. microRNAs: Key Regulators in Plant Responses to Abiotic and Biotic Stresses via Endogenous and Cross-Kingdom Mechanisms. Int J Mol Sci 2024; 25:1154. [PMID: 38256227 PMCID: PMC10816238 DOI: 10.3390/ijms25021154] [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: 11/09/2023] [Revised: 01/03/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
Dramatic shifts in global climate have intensified abiotic and biotic stress faced by plants. Plant microRNAs (miRNAs)-20-24 nucleotide non-coding RNA molecules-form a key regulatory system of plant gene expression; playing crucial roles in plant growth; development; and defense against abiotic and biotic stress. Moreover, they participate in cross-kingdom communication. This communication encompasses interactions with other plants, microorganisms, and insect species, collectively exerting a profound influence on the agronomic traits of crops. This article comprehensively reviews the biosynthesis of plant miRNAs and explores their impact on plant growth, development, and stress resistance through endogenous, non-transboundary mechanisms. Furthermore, this review delves into the cross-kingdom regulatory effects of plant miRNAs on plants, microorganisms, and pests. It proceeds to specifically discuss the design and modification strategies for artificial miRNAs (amiRNAs), as well as the protection and transport of miRNAs by exosome-like nanovesicles (ELNVs), expanding the potential applications of plant miRNAs in crop breeding. Finally, the current limitations associated with harnessing plant miRNAs are addressed, and the utilization of synthetic biology is proposed to facilitate the heterologous expression and large-scale production of miRNAs. This novel approach suggests a plant-based solution to address future biosafety concerns in agriculture.
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Affiliation(s)
- Tianze Ding
- Zhengzhou Research Base, National Key Laboratory of Cotton Bio-Breeding and Integrated Utilization, School of Agricultural Sciences, Zhengzhou University, Zhengzhou 450001, China; (T.D.); (W.L.); (F.L.)
- Institute of Cotton Research, Chinese Academy of Agricultural Sciences, Anyang 455000, China
| | - Wenkang Li
- Zhengzhou Research Base, National Key Laboratory of Cotton Bio-Breeding and Integrated Utilization, School of Agricultural Sciences, Zhengzhou University, Zhengzhou 450001, China; (T.D.); (W.L.); (F.L.)
- Institute of Cotton Research, Chinese Academy of Agricultural Sciences, Anyang 455000, China
| | - Fuguang Li
- Zhengzhou Research Base, National Key Laboratory of Cotton Bio-Breeding and Integrated Utilization, School of Agricultural Sciences, Zhengzhou University, Zhengzhou 450001, China; (T.D.); (W.L.); (F.L.)
- Institute of Cotton Research, Chinese Academy of Agricultural Sciences, Anyang 455000, China
| | - Maozhi Ren
- Zhengzhou Research Base, National Key Laboratory of Cotton Bio-Breeding and Integrated Utilization, School of Agricultural Sciences, Zhengzhou University, Zhengzhou 450001, China; (T.D.); (W.L.); (F.L.)
- Institute of Cotton Research, Chinese Academy of Agricultural Sciences, Anyang 455000, China
| | - Wenjing Wang
- Zhengzhou Research Base, National Key Laboratory of Cotton Bio-Breeding and Integrated Utilization, School of Agricultural Sciences, Zhengzhou University, Zhengzhou 450001, China; (T.D.); (W.L.); (F.L.)
- Institute of Cotton Research, Chinese Academy of Agricultural Sciences, Anyang 455000, China
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Hashemi ZS, Moghadam MF, Khalili S, Hashemi SM, Sepehr KS, Sadroddiny E. Distinctive Expression of MetastamiRs in Breast Cancer Mesenchymal Stem Cells Isolated from Solid Tumor. Curr Stem Cell Res Ther 2024; 19:1525-1534. [PMID: 38265389 DOI: 10.2174/011574888x272313231124063458] [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: 07/15/2023] [Revised: 09/16/2023] [Accepted: 10/02/2023] [Indexed: 01/25/2024]
Abstract
BACKGROUND MSCs are a part of the tumor microenvironment, which secrete cytokines and chemokines. They can affect metastasis and the growth of tumors. metastamiRs are newly recognized regulatory elements of the metastasis pathway which are involved in epithelial-to-mesenchymal transition (EMT). OBJECTIVE In the present study, we aimed to assess the expression profile of metastamiRs in the context of MSCs in correlation with their invasion and migration power. METHODS Tumor-isolated BC-MSCs and normal human mammary epithelial cells (HMECs) along with MCF-7, MDA-MB231, and MCF-10A cells were prepared and confirmed for their identity. The cells were assessed for CD44+CD24¯ percentage, Oct-4, and Survivin expression. GEO, KEGG, and TCGA databases were investigated to detect differential miR-expressions. Real- time PCR for 13 miRs was performed using LNA primers. Ultimately, Transwell-Matrigel assays as used to assess the level of migration and invasion. RESULTS Our results indicated that some oncomiRs like miR-10b were upregulated in BC-MSCs, while the levels of miR-373 and miR-520c were similar to the MCF-10A. Generally, miR-200 family members were on lower levels compared to the other miR-suppressor (miR-146a, 146b, and 335). miR-31 and 193b were up-regulated in MCF-10A. The most invasiveness was observed in the MDA-MB231 cell line. CONCLUSION We have demonstrated that the miR-expression levels of BC-MSCs are somewhat in between MCF-7 and MDA-MB231 miR-expression levels. This could be the logic behind the moderate level of invasion in BC-MSCs. Therefore, miR-therapy approaches such as miR-mimic or antagomiRs could be used for BC-MSCs in clinical cancer therapy.
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Affiliation(s)
- Zahra Sadat Hashemi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- ATMP Department, Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran
- Student's Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Forouzandeh Moghadam
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saeed Khalili
- Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran, Iran
| | - Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Koushan Sineh Sepehr
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Esmaeil Sadroddiny
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
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8
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Sellner F, Compérat E, Klimpfinger M. Genetic and Epigenetic Characteristics in Isolated Pancreatic Metastases of Clear-Cell Renal Cell Carcinoma. Int J Mol Sci 2023; 24:16292. [PMID: 38003482 PMCID: PMC10671160 DOI: 10.3390/ijms242216292] [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: 10/19/2023] [Revised: 11/09/2023] [Accepted: 11/11/2023] [Indexed: 11/26/2023] Open
Abstract
Isolated pancreatic metastases of renal cell carcinoma (IsPMRCC) are a rare manifestation of metastatic, clear-cell renal cell carcinoma (RCC) in which distant metastases occur exclusively in the pancreas. In addition to the main symptom of the isolated occurrence of pancreatic metastases, the entity surprises with additional clinical peculiarities: (a) the unusually long interval of about 9 years between the primary RCC and the onset of pancreatic metastases; (b) multiple pancreatic metastases occurring in 36% of cases; (c) favourable treatment outcomes with a 75% 5-year survival rate; and (d) volume and growth-rate dependent risk factors generally accepted to be relevant for overall survival in metastatic surgery are insignificant in isPMRCC. The genetic and epigenetic causes of exclusive pancreatic involvement have not yet been investigated and are currently unknown. Conversely, according to the few available data in the literature, the following genetic and epigenetic peculiarities can already be identified as the cause of the protracted course: 1. high genetic stability of the tumour cell clones in both the primary tumour and the pancreatic metastases; 2. a low frequency of copy number variants associated with aggressiveness, such as 9p, 14q and 4q loss; 3. in the chromatin-modifying genes, a decreased rate of PAB1 (3%) and an increased rate of PBRM1 (77%) defects are seen, a profile associated with a favourable course; 4. an increased incidence of KDM5C mutations, which, in common with increased PBRM1 alterations, is also associated with a favourable outcome; and 5. angiogenetic biomarkers are increased in tumour tissue, while inflammatory biomarkers are decreased, which explains the good response to TKI therapy and lack of sensitivity to IT.
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Affiliation(s)
- Franz Sellner
- Department of General, Visceral and Vascular Surgery, Clinic Favoriten Vienna, Kaiser Franz Josef Hospital, 1100 Vienna, Austria
| | - Eva Compérat
- Clinical Institute of Pathology, Medical University Vienna, 1090 Vienna, Austria
| | - Martin Klimpfinger
- Clinical Institute of Pathology, Medical University Vienna, 1090 Vienna, Austria
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Kaba M, Pirinççi N, Demir M, Kaba S, Oztuzcu S, Verep S. The relationship between microRNAs and bladder cancer: are microRNAs useful to predict bladder cancer in suspicious patients? Int Urol Nephrol 2023; 55:2483-2491. [PMID: 37338656 DOI: 10.1007/s11255-023-03666-2] [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: 04/29/2023] [Accepted: 06/05/2023] [Indexed: 06/21/2023]
Abstract
PURPOSE Recent studies indicate that circulating micro RNAs (miRNAs) are novel class of non-invasive biomarkers with diagnostic and prognostic information. We evaluated the miRNA expressions in bladder cancer (BC) and their associations with disease diagnosis. METHODS We profiled the expressions of 379 miRNAs in the plasma samples from patients with non-muscle invasive bladder cancer (NMIBC) (n = 34) and non-malignant urological diseases as a control group (n = 32). Patients were evaluated regarding with age, miRNA expressions, by using descriptive statistics. miRNA expression in extracted RNA was quantified using the NanoString nCounter Digital Analyzer. RESULTS The analysis of plasma miRNA levels in the marker identification cohort indicated that plasma (miR-1260a, let-7a-3p miR-196b-5p, miR-196a-5p, miR-99a-5p, miR-615-5p, miR-4301, miR-28-3p, miR-4538, miR-1233-3p, miR-4732-5p, miR-1913, miR-1280) levels were increased in NMIBC patients compared to control subjects. There were no significant differences other parameters studied between groups. CONCLUSIONS The analysis of serum plasma miRNA (miR-1260a, let-7a-3p miR-196b-5p, miR-196a-5p, miR-99a-5p, miR-615-5p, miR-4301, miR-28-3p, miR-4538, miR-1233-3p, miR-4732-5p, miR-1913, miR-1280) levels could be useful plasma biomarkers for BC.
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Affiliation(s)
- Mehmet Kaba
- Department of Urology, Private Yuzyil Gebze Hospital, Sultan Orhan Mahallesi, Ilyasbey Cd. No:38, 41400, Gebze, Kocaeli, Turkey
| | - Necip Pirinççi
- Department of Urology, Fırat University Medical Faculty, Elazıg, Turkey
| | - Murat Demir
- Department of Urology, Van Yuzuncuyil University Dursun Odabası Medical Center, Van, Turkey
| | - Sultan Kaba
- Department of Pediatry, Okan University Hospital, Section of Pediatric Endocrinology, Istanbul, Turkey
| | - Serdar Oztuzcu
- Department of Medical Biology, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Samed Verep
- Department of Urology, Private Yuzyil Gebze Hospital, Sultan Orhan Mahallesi, Ilyasbey Cd. No:38, 41400, Gebze, Kocaeli, Turkey.
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Ghionescu AV, Sorop A, Dima SO. The pivotal role of EMT-related noncoding RNAs regulatory axes in hepatocellular carcinoma. Front Pharmacol 2023; 14:1270425. [PMID: 37767397 PMCID: PMC10520284 DOI: 10.3389/fphar.2023.1270425] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 08/30/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a major health problem worldwide, being the leading cause of cancer-related deaths, with limited treatment options, especially in its advanced stages. Tumor resistance is closely associated with the activation of the EMT phenomenon and its reversal, being modulated by different molecules, including noncoding RNAs (ncRNAs). Noncoding RNAs have the potential to function as both tumor suppressors and oncogenic molecules, controlling the malignant potential of HCC cells. Basically, these molecules circulate in the tumor microenvironment, encapsulated in exosomes. Their impact on cell biology is more significant than originally expected, which makes related research rather complex. The temporal and spatial expression patterns, precise roles and mechanisms of specific ncRNAs encapsulated in exosomes remain primarily unknown in different stages of the disease. This review aims to highlight the recent advances in ncRNAs related to EMT and classifies the described mechanism as direct and indirect, for a better summarization. Moreover, we provide an overview of current research on the role of ncRNAs in several drug resistance-related pathways, including the emergence of resistance to sorafenib, doxorubicin, cisplatin and paclitaxel therapy. Nevertheless, we comprehensively discuss the underlying regulatory mechanisms of exosomal ncRNAs in EMT-HCC via intercellular communication pathways.
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Affiliation(s)
| | - Andrei Sorop
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
| | - Simona Olimpia Dima
- Center of Excellence in Translational Medicine, Fundeni Clinical Institute, Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Escuin D, López-Vilaró L, Bell O, Mora J, García-Valdecasas B, Moral A, Clos M, Boronat L, Arqueros C, Barnadas A. Circulating miRNA Expression Is Inversely Correlated with Tumor Tissue or Sentinel Lymph Nodes in Estrogen Receptor-Positive Early Breast Cancer Patients. Int J Mol Sci 2023; 24:13293. [PMID: 37686099 PMCID: PMC10487825 DOI: 10.3390/ijms241713293] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/20/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
The deregulation of microRNAs (miRNAs) is associated with the various steps of the metastatic process. In addition, circulating miRNAs are remarkably stable in peripheral blood, making them ideal noninvasive biomarkers for disease diagnosis. Here, we performed a proof-of-principle study to determine whether tumor-tissue-derived miRNAs are traceable to plasma in ER-positive early breast cancer patients. We performed RNA-sequencing on 30 patients for whom plasma, sentinel lymph nodes (SLNs) and tumor tissue were available. We carried out differential expression, gene ontology and enrichment analyses. Our results show that circulating miRNAs are inversely expressed compared with tumor tissue or SLNs obtained from the same patients. Our differential expression analysis shows the overall downregulation of circulating miRNAs. However, the expression of miR-643a-3p and miR-223 was up-regulated in patients with positive SLNs. Furthermore, gene ontology analysis showed the significant enrichment of biological processes associated with the regulation of epithelial cell proliferation and transcriptional regulation commonly involved in the promotion of metastases. Our results suggest the potential role of several circulating miRNAs as surrogate markers of lymph node metastases in early breast cancer patients. Further preclinical and clinical studies are required to understand the biological significance of the most significant miRNAs and to validate our results in a larger cohort of patients.
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Affiliation(s)
- Daniel Escuin
- Institut d’Investigació Biomèdica Sant Pau (IIB-Sant Pau), 08041 Barcelona, Spain; (L.L.-V.); (O.B.)
| | - Laura López-Vilaró
- Institut d’Investigació Biomèdica Sant Pau (IIB-Sant Pau), 08041 Barcelona, Spain; (L.L.-V.); (O.B.)
- Department of Pathology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain
| | - Olga Bell
- Institut d’Investigació Biomèdica Sant Pau (IIB-Sant Pau), 08041 Barcelona, Spain; (L.L.-V.); (O.B.)
| | - Josefina Mora
- Department of Biochemistry, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain;
| | - Bárbara García-Valdecasas
- Department of Surgery, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (B.G.-V.); (A.M.); (M.C.)
| | - Antonio Moral
- Department of Surgery, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (B.G.-V.); (A.M.); (M.C.)
- Faculty of Medicine, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain
| | - Montserrat Clos
- Department of Surgery, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (B.G.-V.); (A.M.); (M.C.)
| | - Laia Boronat
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (L.B.); (C.A.)
| | - Cristina Arqueros
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (L.B.); (C.A.)
| | - Agustí Barnadas
- Institut d’Investigació Biomèdica Sant Pau (IIB-Sant Pau), 08041 Barcelona, Spain; (L.L.-V.); (O.B.)
- Faculty of Medicine, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain; (L.B.); (C.A.)
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
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12
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Deng T, Su S, Yuan X, He J, Huang Y, Ma J, Wang J. Structural mechanism of R2D2 and Loqs-PD synergistic modulation on DmDcr-2 oligomers. Nat Commun 2023; 14:5228. [PMID: 37633971 PMCID: PMC10460399 DOI: 10.1038/s41467-023-40919-1] [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: 11/20/2022] [Accepted: 08/16/2023] [Indexed: 08/28/2023] Open
Abstract
Small interference RNAs are the key components of RNA interference, a conserved RNA silencing or viral defense mechanism in many eukaryotes. In Drosophila melanogaster, Dicer-2 (DmDcr-2)-mediated RNAi pathway plays important roles in defending against viral infections and protecting genome integrity. During the maturation of siRNAs, two cofactors can regulate DmDcr-2's functions: Loqs-PD that is required for dsRNA processing, and R2D2 that is essential for the subsequent loading of siRNAs into effector Ago2 to form RISC complexes. However, due to the lack of structural information, it is still unclear whether R2D2 and Loqs-PD affect the functions of DmDcr-2 simultaneously. Here we present several cryo-EM structures of DmDcr-2/R2D2/Loqs-PD complex bound to dsRNAs with various lengths by the Helicase domain. These structures revealed that R2D2 and Loqs-PD can bind to different regions of DmDcr-2 without interfering with each other. Furthermore, the cryo-EM results demonstrate that these complexes can form large oligomers and assemble into fibers. The formation and depolymerization of these oligomers are associated with ATP hydrolysis. These findings provide insights into the structural mechanism of DmDcr-2 and its cofactors during siRNA processing.
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Affiliation(s)
- Ting Deng
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Centre of Genetics and Development, Department of Biochemistry and Biophysics, Institute of Plant Biology, School of Life Sciences, Fudan University, 200438, Shanghai, China
| | - Shichen Su
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Centre of Genetics and Development, Department of Biochemistry and Biophysics, Institute of Plant Biology, School of Life Sciences, Fudan University, 200438, Shanghai, China
| | - Xun Yuan
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai Research Center of Biliary Tract Disease, Department of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinqiu He
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Centre of Genetics and Development, Department of Biochemistry and Biophysics, Institute of Plant Biology, School of Life Sciences, Fudan University, 200438, Shanghai, China
| | - Ying Huang
- Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai Research Center of Biliary Tract Disease, Department of General Surgery, Xinhua Hospital, Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinbiao Ma
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Centre of Genetics and Development, Department of Biochemistry and Biophysics, Institute of Plant Biology, School of Life Sciences, Fudan University, 200438, Shanghai, China.
| | - Jia Wang
- Ministry of Education Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Beijing Frontier Research Center of Biological Structures, School of Life Sciences, Tsinghua University, Beijing, China.
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13
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Wu S, Wu Y, Deng S, Lei X, Yang X. Emerging roles of noncoding RNAs in human cancers. Discov Oncol 2023; 14:128. [PMID: 37439905 DOI: 10.1007/s12672-023-00728-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 06/14/2023] [Indexed: 07/14/2023] Open
Abstract
Studies have found that RNA encoding proteins only account for a small part of the total number, most RNA is non-coding RNA, and non-coding RNA may affect the occurrence and development of human cancers by affecting gene expression, therefore play an important role in human pathology. At present, ncRNAs studied include miRNA, circRNA, lncRNA, piRNA, and snoRNA, etc. After decades of research, the basic role of these ncRNAs in many cancers has been clear. As far as we know, the role of miRNAs in cancer is one of the hottest research directions, however, it is also found that the imbalance of ncRNAs will affect the occurrence of gastric cancer, breast cancer, lung cancer, meanwhile, it may also affect the prognosis of these cancers. Therefore, the study of ncRNAs in cancers may help to find new cancer diagnostic and treatment methods. Here, we reviewed the biosynthesis and characteristics of miRNA, cricRNA, and lncRNA etc., their roles in human cancers, as well as the mechanism through which these ncRNAs affect human cancers.
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Affiliation(s)
- Shijie Wu
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China
| | - Yiwen Wu
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China
| | - Sijun Deng
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China
| | - Xiaoyong Lei
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China
| | - Xiaoyan Yang
- School of Pharmaceutical Science, Hengyang Medical College, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, 28 Western Changsheng Road, Hengyang, 421001, Hunan, People's Republic of China.
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14
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Hu Q, Huang T. Regulation of the Cell Cycle by ncRNAs Affects the Efficiency of CDK4/6 Inhibition. Int J Mol Sci 2023; 24:ijms24108939. [PMID: 37240281 DOI: 10.3390/ijms24108939] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Cyclin-dependent kinases (CDKs) regulate cell division at multiple levels. Aberrant proliferation induced by abnormal cell cycle is a hallmark of cancer. Over the past few decades, several drugs that inhibit CDK activity have been created to stop the development of cancer cells. The third generation of selective CDK4/6 inhibition has proceeded into clinical trials for a range of cancers and is quickly becoming the backbone of contemporary cancer therapy. Non-coding RNAs, or ncRNAs, do not encode proteins. Many studies have demonstrated the involvement of ncRNAs in the regulation of the cell cycle and their abnormal expression in cancer. By interacting with important cell cycle regulators, preclinical studies have demonstrated that ncRNAs may decrease or increase the treatment outcome of CDK4/6 inhibition. As a result, cell cycle-associated ncRNAs may act as predictors of CDK4/6 inhibition efficacy and perhaps present novel candidates for tumor therapy and diagnosis.
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Affiliation(s)
- Qingyi Hu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tao Huang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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15
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Mafi A, Keshavarzmotamed A, Hedayati N, Boroujeni ZY, Reiter RJ, Dehmordi RM, Aarabi MH, Rezaee M, Asemi Z. Melatonin targeting non-coding RNAs in cancer: Focus on mechanisms and potential therapeutic targets. Eur J Pharmacol 2023; 950:175755. [PMID: 37119959 DOI: 10.1016/j.ejphar.2023.175755] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/15/2023] [Accepted: 04/26/2023] [Indexed: 05/01/2023]
Abstract
Despite, melatonin is mainly known as a regulatory factor for circadian rhythm, its notable role in other fundamental biological processes, such as redox homeostasis and programmed cell death, has been found. In this line, a growing body of evidence indicated that melatonin could apply an inhibitory effect on the tumorigenic processes. Hence, melatonin might be considered an efficient adjuvant agent for cancer treatment. Besides, the physiological and pathological functions of non-coding RNAs (ncRNAs) in various disease, particularly cancers, have been expanded over the past two decades. It is well-established that ncRNAs can modulate the gene expression at various levels, thereby, ncRNAs. can regulate the numerous biological processes, including cell proliferation, cell metabolism, apoptosis, and cell cycle. Recently, targeting the ncRNAs expression provides a novel insight in the therapeutic approaches for cancer treatment. Moreover, accumulating investigations have revealed that melatonin could impact the expression of different ncRNAs in a multiple disorders, including cancer. Therefore, in the precent study, we discuss the potential roles of melatonin in modulating the expression of ncRNAs and the related molecular pathways in different types of cancer. Also, we highlighted its importance in therapeutic application and translational medicine in cancer treatment.
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Affiliation(s)
- Alireza Mafi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Nutrition and Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | | | - Neda Hedayati
- School of Medicine, Iran University of Medical Science, Tehran, Iran.
| | - Zahra Yeganeh Boroujeni
- School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health. Long School of Medicine, San Antonio, TX, USA.
| | - Rohollah Mousavi Dehmordi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Mohammad-Hossein Aarabi
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Malihe Rezaee
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Tehran Heart Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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16
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Golubovic A, Tsai S, Li B. Bioinspired Lipid Nanocarriers for RNA Delivery. ACS BIO & MED CHEM AU 2023; 3:114-136. [PMID: 37101812 PMCID: PMC10125326 DOI: 10.1021/acsbiomedchemau.2c00073] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/20/2022] [Accepted: 12/21/2022] [Indexed: 04/28/2023]
Abstract
RNA therapy is a disruptive technology comprising a rapidly expanding category of drugs. Further translation of RNA therapies to the clinic will improve the treatment of many diseases and help enable personalized medicine. However, in vivo delivery of RNA remains challenging due to the lack of appropriate delivery tools. Current state-of-the-art carriers such as ionizable lipid nanoparticles still face significant challenges, including frequent localization to clearance-associated organs and limited (1-2%) endosomal escape. Thus, delivery vehicles must be improved to further unlock the full potential of RNA therapeutics. An emerging strategy is to modify existing or new lipid nanocarriers by incorporating bioinspired design principles. This method generally aims to improve tissue targeting, cellular uptake, and endosomal escape, addressing some of the critical issues facing the field. In this review, we introduce the different strategies for creating bioinspired lipid-based RNA carriers and discuss the potential implications of each strategy based on reported findings. These strategies include incorporating naturally derived lipids into existing nanocarriers and mimicking bioderived molecules, viruses, and exosomes. We evaluate each strategy based on the critical factors required for delivery vehicles to succeed. Finally, we point to areas of research that should be furthered to enable the more successful rational design of lipid nanocarriers for RNA delivery.
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Affiliation(s)
- Alex Golubovic
- Department
of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada
| | - Shannon Tsai
- Department
of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada
| | - Bowen Li
- Department
of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada
- Institute
of Biomedical Engineering, University of
Toronto, Toronto, Ontario M5S 3G9, Canada
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17
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Zhang Y, Rabinovsky R, Wei Z, El Fatimy R, Deforzh E, Luan B, Peshkin L, Uhlmann EJ, Krichevsky AM. Secreted PGK1 and IGFBP2 contribute to the bystander effect of miR-10b gene editing in glioma. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 31:265-275. [PMID: 36700043 PMCID: PMC9852814 DOI: 10.1016/j.omtn.2022.12.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 12/31/2022] [Indexed: 01/03/2023]
Abstract
MicroRNA-10b (miR-10b) is an essential glioma driver and one of the top candidates for targeted therapies for glioblastoma and other cancers. This unique miRNA controls glioma cell cycle and viability via an array of established conventional and unconventional mechanisms. Previously reported CRISPR-Cas9-mediated miR-10b gene editing of glioma cells in vitro and established orthotopic glioblastoma in mouse models demonstrated the efficacy of this approach and its promise for therapy development. However, therapeutic gene editing in patients' brain tumors may be hampered, among other factors, by the imperfect delivery and distribution of targeting vectors. Here, we demonstrate that miR-10b gene editing in glioma cells triggers a potent bystander effect that leads to the selective cell death of the unedited glioma cells without affecting the normal neuroglial cells. The effect is mediated by the secreted miR-10b targets phosphoglycerate kinase 1 (PGK1) and insulin-like growth factor binding protein 2 (IGFBP2) that block cell-cycle progression and induce glioma cell death. These findings further support the feasibility of therapeutic miR-10b editing without the need to target every cell of the tumor.
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Affiliation(s)
- Yanhong Zhang
- Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Harvard Initiative for RNA Medicine, Boston, MA 02115, USA
| | - Rosalia Rabinovsky
- Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Harvard Initiative for RNA Medicine, Boston, MA 02115, USA
| | - Zhiyun Wei
- Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Harvard Initiative for RNA Medicine, Boston, MA 02115, USA
| | - Rachid El Fatimy
- Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Harvard Initiative for RNA Medicine, Boston, MA 02115, USA
| | - Evgeny Deforzh
- Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Harvard Initiative for RNA Medicine, Boston, MA 02115, USA
| | - Bai Luan
- Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Leonid Peshkin
- Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Erik J. Uhlmann
- Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Harvard Initiative for RNA Medicine, Boston, MA 02115, USA
| | - Anna M. Krichevsky
- Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Harvard Initiative for RNA Medicine, Boston, MA 02115, USA
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18
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Song BF, Xu LZ, Jiang K, Cheng F. MiR-124-3p inhibits tumor progression in prostate cancer by targeting EZH2. Funct Integr Genomics 2023; 23:80. [PMID: 36884182 PMCID: PMC9995421 DOI: 10.1007/s10142-023-00991-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 02/05/2023] [Accepted: 02/16/2023] [Indexed: 03/09/2023]
Abstract
Prostate cancer (PCa) is widespread cancer with significant morbidity and mortality rates. MicroRNAs (miRNAs) have been identified as important post-transcriptional modulators in various malignancies. This study investigated the miR-124-3p effect on PCa cell proliferation, infiltration, and apoptosis. EZH2 and miR-124-3p expression levels were measured in PCa tissues. PCa cell lines DU145 and PC3 were transfected with miR-124-3p inhibitors or analogs. EZH2 and miR-124-3p linkage was validated by conducting the luciferase enzyme reporter test. The cell viability and apoptosis were assessed by flow cytometry and MTT test. Cell movement was noted during infiltration using transwell assays. EZH2, AKT, and mTOR contents were assessed using qRT-PCR and western blotting. In clinical PCa specimens, miR-124-3p and EZH2 contents were inversely correlated. Further research has demonstrated that EZH2 is the miR-124-3p direct target. Furthermore, miR-124-3p overexpression reduced EZH2 levels and lowered cell viability, infiltration, and promoted cell death, whereas miR-124-3p silencing had the opposite effect. Overexpression of miR-124-3p decreased the phosphorylation level of AKT and mTOR, whereas miR-124-3p downregulation produced the opposite result. Our findings depict that miR-124-3p prevents PCa proliferative and invasive processes while promoting apoptosis by targeting EZH2.
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Affiliation(s)
- Bao-Feng Song
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Li-Zhe Xu
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China
| | - Kun Jiang
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China.
| | - Fan Cheng
- Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, People's Republic of China.
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19
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Exosomal miRNA-155 and miRNA-146a are promising prognostic biomarkers of the severity of hemorrhagic fever with renal syndrome. Noncoding RNA Res 2023; 8:75-82. [DOI: 10.1016/j.ncrna.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/14/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022] Open
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20
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Innocenti T, Bigagli E, Lynch EN, Galli A, Dragoni G. MiRNA-Based Therapies for the Treatment of Inflammatory Bowel Disease: What Are We Still Missing? Inflamm Bowel Dis 2023; 29:308-323. [PMID: 35749310 DOI: 10.1093/ibd/izac122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Indexed: 02/05/2023]
Abstract
Micro-RNAs (miRNAs) are noncoding RNAs usually 24-30 nucleotides long that play a central role in epigenetic mechanisms of inflammatory diseases and cancers. Recently, several studies have assessed the involvement of miRNAs in the pathogenesis of inflammatory bowel disease (IBD) and colitis-associated neoplasia. Particularly, it has been shown that many members of miRNAs family are involved in the pathways of inflammation and fibrogenesis of IBD; therefore, their use as inflammatory and fibrosis biomarkers has been postulated. In light of these results, the role of miRNAs in IBD therapy has been proposed and is currently under investigation with many in vitro and in vivo studies, murine models, and a phase 2a trial. The accumulating data have pushed miRNA-based therapy closer to clinical practice, although many open questions remain. With this systematic review, we discuss the current knowledge about the therapeutic effects of miRNAs mimicking and inhibition, and we explore the new potential targets of miRNA family for the treatment of inflammation and fibrosis in IBD.
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Affiliation(s)
- Tommaso Innocenti
- IBD Referral Center, Gastroenterology Department, Careggi University Hospital, Florence, Italy.,Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Elisabetta Bigagli
- Section of Pharmacology and Toxicology, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
| | - Erica Nicola Lynch
- IBD Referral Center, Gastroenterology Department, Careggi University Hospital, Florence, Italy.,Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Gabriele Dragoni
- IBD Referral Center, Gastroenterology Department, Careggi University Hospital, Florence, Italy.,Gastroenterology Research Unit, Department of Experimental and Clinical Biochemical Sciences "Mario Serio", University of Florence, Florence, Italy
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21
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Wang XJ, Zhang D, Yang YT, Li XY, Li HN, Zhang XP, Long JY, Lu YQ, Liu L, Yang G, Liu J, Hong J, Wu HG, Ma XP. Suppression of microRNA-222-3p ameliorates ulcerative colitis and colitis-associated colorectal cancer to protect against oxidative stress via targeting BRG1 to activate Nrf2/HO-1 signaling pathway. Front Immunol 2023; 14:1089809. [PMID: 36776858 PMCID: PMC9911687 DOI: 10.3389/fimmu.2023.1089809] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/16/2023] [Indexed: 01/28/2023] Open
Abstract
Oxidative stress is an important pathogenic factor in ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC), further impairing the entire colon. Intestinal epithelial cells (IECs) are crucial components of innate immunity and play an important role in maintaining intestinal barrier function. Recent studies have indicated that microRNA-222-3p (miR-222-3p) is increased in colon of UC and colorectal cancer (CRC) patients, and miR-222-3p is a crucial regulator of oxidative stress. However, whether miR-222-3p influences IEC oxidative stress in UC and CAC remains unknown. This study investigated the effect of miR-222-3p on the regulation of IEC oxidative stress in UC and CAC. An in vitro inflammation model was established in NCM460 colonic cells, mouse UC and CAC models were established in vivo, and IECs were isolated. The biological role and mechanism of miR-222-3p-mediated oxidative stress in UC and CAC were determined. We demonstrated that miR-222-3p expression was notably increased in dextran sulfate sodium (DSS)-induced NCM460 cells and IECs from UC and CAC mice. In vitro, these results showed that the downregulation of miR-222-3p reduced oxidative stress, caspase-3 activity, IL-1β and TNF-α in DSS-induced NCM460 cells. We further identified BRG1 as the target gene of miR-222-3p, and downregulating miR-222-3p alleviated DSS-induced oxidative injury via promoting BRG1-mediated activation Nrf2/HO-1 signaling in NCM460 cells. The in vivo results demonstrated that inhibiting miR-222-3p in IECs significantly relieved oxidative stress and inflammation in the damaged colons of UC and CAC mice, as evidenced by decreases in ROS, MDA, IL-1β and TNF-α levels and increases in GSH-Px levels. Our study further demonstrated that inhibiting miR-222-3p in IECs attenuated oxidative damage by targeting BRG1 to activate the Nrf2/HO-1 signaling. In summary, inhibiting miR-222-3p in IECs attenuates oxidative stress by targeting BRG1 to activate the Nrf2/HO-1 signaling, thereby reducing colonic inflammation and tumorigenesis.
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Affiliation(s)
- Xue-jun Wang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Dan Zhang
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan-ting Yang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-ying Li
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hong-na Li
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-peng Zhang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jun-yi Long
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yun-qiong Lu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li Liu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Yang
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jie Liu
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jue Hong
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Huan-gan Wu
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiao-peng Ma
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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22
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Lu B, Zhu Y, Wu J, Qiu H, Wang J, Ma Z, Jia K. LncRNA34977 promotes the proliferation, migration, and invasion and inhibits the apoptosis of canine mammary tumors by regulating the expression of miR-8881/ELAVL4. Funct Integr Genomics 2023; 23:31. [PMID: 36604379 PMCID: PMC9816241 DOI: 10.1007/s10142-022-00955-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/07/2023]
Abstract
Long-stranded noncoding RNAs (lncRNAs) play different roles in various diseases. lncRNA34977 has been shown to play a relevant role the development of canine mammary tumors (CMTs). However, the mechanism of lncRNA34977 in canine mammary tumors has not been fully investigated. The aim of this study was to investigate the effects of lncRNA34977 on the proliferation, migration, invasion, and apoptosis of canine mammary tumor (CMT) cells through the regulation of miR-8881/ELAVL4 expression. The apoptosis was detected by an in situ fluorescence assay and flow cytometry. The expression levels were analyzed by RT-qPCR. CCK-8, colony formation, wound healing, and Transwell assays were used to assess the proliferation, migration, and invasion. The expression of protein was detected by western blot. The siRNA-induced silencing of lncRNA34977 promoted the apoptosis of CHMp cells, and in overexpression of lncRNA34977, the result is the opposite. LncRNA34977 has a direct targeting relationship with miR-8881 and that miR-8881 is correlated with ELAVL4. Transfection of miR-8881 mimics inhibited the proliferation, migration, invasion, and promoted the apoptosis of CHMp cells of CHMp cells. In the transfection with miR-8881 inhibitors, the result is the opposite. Co-transfected with lncRNA34977, miR-8881, or ELAVL4, we found that lncRNA34977 could regulate the expression of miR-8881 or ELAVL4. Our study shows that lncRNA34977 promotes the proliferation, migration, and invasion and suppresses the apoptosis of CMT cells by regulating the expression of miR-8881/ELAVL4.
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Affiliation(s)
- Baochun Lu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, Guangzhou, 510642, China.,Guangdong Technological Engineering Research Center for Pet, Guangzhou, 510642, China
| | - Yufan Zhu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, Guangzhou, 510642, China.,Guangdong Technological Engineering Research Center for Pet, Guangzhou, 510642, China
| | - Juye Wu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, Guangzhou, 510642, China.,Guangdong Technological Engineering Research Center for Pet, Guangzhou, 510642, China
| | - Huidan Qiu
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, Guangzhou, 510642, China
| | - Jinyu Wang
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, Guangzhou, 510642, China.,Guangdong Technological Engineering Research Center for Pet, Guangzhou, 510642, China
| | - Zihang Ma
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.,Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, Guangzhou, 510642, China.,Guangdong Technological Engineering Research Center for Pet, Guangzhou, 510642, China
| | - Kun Jia
- College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China. .,Guangdong Provincial Key Laboratory of Prevention and Control for Severe Clinical Animal Diseases, Guangzhou, 510642, China. .,Guangdong Technological Engineering Research Center for Pet, Guangzhou, 510642, China.
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Bilal M, Javaid A, Amjad F, Youssif TA, Afzal S. An overview of prostate cancer (PCa) diagnosis: Potential role of miRNAs. Transl Oncol 2022; 26:101542. [PMID: 36148731 PMCID: PMC9493385 DOI: 10.1016/j.tranon.2022.101542] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/18/2022] [Accepted: 09/07/2022] [Indexed: 12/15/2022] Open
Abstract
Prostate cancer is the second most frequently diagnosed cancer among men worldwide, with the estimated sixth leading cause of cancer death. Despite major advancements in clinical biology and imaging, digital rectal examination (DRE), prostate-specific antigen (PSA), and biopsies indication remain the keystone for screening. Several kits are used to detect genomic changes and non-coding RNAs in the sample. However, its indication remains controversial for screening purposes. There is an urged need for non-invasive biomarkers to implement precision medicine. Recent research shows that miRNAs have an important role in the diagnostic, prognostic, and therapeutic agents as non-invasive biomarkers. Though prostate cancer data remains controversial in other cancer types, such as breast cancer, miR-21 expression is upregulated. Here, we reported a prolonged revision of miRNAs as prostate cancer prognostic, diagnostic, and predictive tools, including data on androgen receptor (AR) signaling, epithelial-mesenchymal transition (EMT) process, and cancer stem cells (CSCs) regulation. The combined utilization of miRNAs with other tests will help patients and clinicians to select the most appropriate personalized treatment and to avoid overdiagnosis and unnecessary biopsies. Future clinical applications of our reported novel miRNAs have a substantial role in the primary diagnosis of prostate cancer to help treatment decisions.
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Affiliation(s)
- Muhammad Bilal
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Suita, Japan; SANKEN (The Institute of Scientific and Industrial Research), Osaka University, Ibaraki, Japan
| | - Aqsa Javaid
- Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan
| | - Farhat Amjad
- Quaid-e-Azam Medical College, Bahawalpur, Pakistan
| | | | - Samia Afzal
- Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
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24
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Roessner A, Franke S, Schreier J, Ullmann S, Karras F, Jechorek D. Genetics and epigenetics in conventional chondrosarcoma with focus on non-coding RNAs. Pathol Res Pract 2022; 239:154172. [DOI: 10.1016/j.prp.2022.154172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 10/14/2022] [Accepted: 10/14/2022] [Indexed: 11/09/2022]
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25
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Qing Y, Yang Y, Ouyang P, Fang C, Fang H, Liao Y, Li H, Wang Z, Du J. Gold Nanoparticle-Based Enzyme-Assisted Cyclic Amplification for the Highly-Sensitive Detection of miRNA-21. BIOSENSORS 2022; 12:bios12090724. [PMID: 36140109 PMCID: PMC9496089 DOI: 10.3390/bios12090724] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 08/28/2022] [Accepted: 09/01/2022] [Indexed: 12/27/2022]
Abstract
Because microRNAs (miRNAs) are biological indicators for the diagnosis, treatment, and monitoring of tumors, cancers, and other diseases, it is significant to develop a rapid, sensitive, and reliable miRNA detection platform. In this study, based on miRNA-21 detection, DNA-a with a 3′ end overhang and Texas Red fluorophore-labeled 5′ end was designed, which reacts with miRNA-21 and hybridizes with exonuclease III (Exo III), where the part connected to miRNA-21 is hydrolyzed, leaving a-DNA. At the same time, miRNA-21 is released to participate in the following reaction, to achieve cyclic amplification. a-DNA reacts with DNA-b conjugated to gold nanoparticles to achieve fluorescence quenching, with the quenching value denoted as F; additionally, after adding DNA-d and linked streptavidin immunomagnetic beads (SIBs), fluorescence recovery was achieved using DNA-c, with the recovered fluorescence recorded as F0. By comparing the difference in the fluorescence (F0 − F) between the two experiments, the amount of DNA-a hydrolyzed to produce a-DNA was established to determine the target miRNA-21 content. Under optimized conditions, by comparing the changes in the fluorescence signal, the developed strategy shows good sensitivity and repeatability, with a detection limit of 18 pM, good discriminative ability and selectivity, and promise for the early diagnosis of breast and intestinal cancers.
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26
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Zhang H, Wang R, Deng Q. miR-29b Regulates Lung Cancer Progression by Downregulating FEM1B and Inhibiting the FOX01/AKT Pathway. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:3110330. [PMID: 36003920 PMCID: PMC9393195 DOI: 10.1155/2022/3110330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 06/30/2022] [Indexed: 12/24/2022]
Abstract
Purpose Lung cancer is a relatively common type of cancer, and the incidence rate has been on the rise in recent years. MicroRNAs are a class of endogenous small RNA molecules, which are essential for the posttranscriptional regulation of genes. miR-29b is closely related to the occurrence and development of tumors, including prostate cancer, colon cancer, and breast cancer. However, few studies have been performed to explore the expression and pathway of miR-29b in non-small-cell lung cancer (NSCLC). Methods Using bioinformatics analysis, we found that patients with low relative expression of the miR-29b gene have a low long-term survival rate. The results of in vitro research showed that when miR-29b expression was upregulated, the invasion, migration, and proliferation of A549 and NCI-H-1792 cells was inhibited, and the apoptosis was accelerated. Results The results showed that FEM1B is a miR-29b target gene, and the expressions of FEM1B and miR-29b were negatively correlated. Like the upregulation of miR-29b expression, silencing the FEM1B expression could also impair the invasion, migration, and proliferation abilities of A549 and NCI-H-1792 cells. When FEM1B expression was restored, the inhibitory effect of miR-29b could be reversed. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot (WB) analysis showed that overexpression of miR-29b could inhibit the expression of FEM1B, AKT, vascular endothelial growth factor (VEGF), and Sirt3 in A549 and NCI-H-1792 cells and upregulate the expression of FOXO1 protein. Conclusion The results of this study indicate that miR-29b inhibits the proliferation and deterioration of NSCLC cells by targeting FEM1B and inhibiting the activation of the FOXO1/AKT pathway. miR-29b may become a new target for the clinical diagnosis and treatment of lung cancer, and it is expected to become a new inhibitor of NSCLC.
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Affiliation(s)
- Huanrong Zhang
- Department of Thoracic Surgery, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Rong Wang
- Department of Thoracic Surgery, Meizhou People's Hospital (Huangtang Hospital), Meizhou Academy of Medical Sciences, Meizhou, China
| | - Qiuhua Deng
- The Translational Medicine Laboratory, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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27
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Ouyang P, Qing Y, Zou S, Fang C, Han J, Yang Y, Li H, Wang Z, Du J. Sensitive detection of miR-122 via toehold-promoted strand displacement reaction and enzyme-assisted cycle amplification. Biochem Eng J 2022. [DOI: 10.1016/j.bej.2022.108576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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28
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The Role of MicroRNA in the Regulation of Tumor Epithelial–Mesenchymal Transition. Cells 2022; 11:cells11131981. [PMID: 35805066 PMCID: PMC9265548 DOI: 10.3390/cells11131981] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 06/13/2022] [Accepted: 06/14/2022] [Indexed: 02/01/2023] Open
Abstract
Consistently, the high metastasis of cancer cells is the bottleneck in the process of tumor treatment. In this process of metastasis, a pivotal role is executed by epithelial–mesenchymal transition (EMT). The epithelial-to-mesenchymal transformation was first proposed to occur during embryonic development. Later, its important role in explaining embryonic developmental processes was widely reported. Recently, EMT and its intermediate state were also identified as crucial drivers in tumor progression with the gradual deepening of research. To gain insights into the potential mechanism, increasing attention has been focused on the EMT-related transcription factors. Correspondingly, miRNAs target transcription factors to control the EMT process of tumor cells in different types of cancers, while there are still many exciting and challenging questions about the phenomenon of microRNA regulation of cancer EMT. We describe the relevant mechanisms of miRNAs regulating EMT, and trace the regulatory roles and functions of major EMT-related transcription factors, including Snail, Twist, zinc finger E-box-binding homeobox (ZEB), and other families. In addition, on the basis of the complex regulatory network, we hope that the exploration of the regulatory relationship of non-transcription factors will provide a better understanding of EMT and cancer metastasis. The identification of the mechanism leading to the activation of EMT programs during diverse disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Here, we summarize the recent progress in this direction, with a promising path for further insight into this fast-moving field.
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29
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Tang BJ, Sun B, Chen L, Xiao J, Huang ST, Xu P. The Landscape of Exosome-Derived Non-Coding RNA in Leukemia. Front Pharmacol 2022; 13:912303. [PMID: 35784717 PMCID: PMC9240230 DOI: 10.3389/fphar.2022.912303] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/27/2022] [Indexed: 11/24/2022] Open
Abstract
Leukemia is a group of life-threatening hematological malignancies which is currently incurable and often accompanied by drug resistance or disease relapse. Understanding the pathogenesis of leukemia and finding specific therapeutic targets and biomarkers is of great importance to improve the clinical efficacy of leukemia. Exosome-derived ncRNAs have been demonstrated as critical components of intercellular communication and function as key facilitators in the leukemia biological process. This review outlines the current investigations of exosomal ncRNAs (including miRNA, circRNA, and lncRNA) as important mediators of leukemia and potential therapeutic targets and biomarkers for leukemia treatment. Moreover, we generally analyze the prospects and challenges for exosomal ncRNAs from the aspects of research and clinical application.
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Affiliation(s)
- Bing-Jie Tang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Bao Sun
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Lei Chen
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Jie Xiao
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Shu-Ting Huang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Ping Xu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- *Correspondence: Ping Xu,
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30
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Guo T, Xiang Y, Lu H, Huang M, Liu F, Fang M, Liu J, Tang Y, Li X, Yang F. Interfacial DNA Framework-Enhanced Background-to-Signal Transition for Ultrasensitive and Specific Micro-RNA Detection. ACS APPLIED MATERIALS & INTERFACES 2022; 14:18209-18218. [PMID: 35416047 DOI: 10.1021/acsami.2c03075] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Interfacial DNA self-assembly is fundamental to solid nucleic acid biosensors, whereas how to improve the signal-to-noise ratio has always been a challenge, especially in the charge-based electrochemical DNA sensors because of the large noise from the negatively charged DNA capture probes. Here, we report a DNA framework-reversed signal-gain strategy through background-to-signal transition for ultrasensitive and highly specific electrical detection of microRNAs (miRNAs) in blood. By using a model of enzyme-catalyzed deposition of conductive molecules (polyaniline) targeting to DNA, we observed the highest signal contribution per unit area by the highly charged three-dimensional (3D) tetrahedral DNA framework probe, relative to the modest of two-dimensional (2D) polyA probe and the lowest of one-dimensional (1D) single-stranded (ss)DNA probe, suggesting the positive correlation of background DNA charge with signal enhancement. Using such an effective signal-transition design, the DNA framework-based electrochemical sensor achieves ultrasensitive miRNAs detection with sensitivity up to 0.29 fM (at least 10-fold higher than that with 1D ssDNA or 2D polyA probes) and high specificity with single-base resolution. More importantly, this high-performance sensor allows for a generalized sandwich detection of tumor-associated miRNAs in the complex matrices (multiple cell lysates and blood serum) and further distinguishes the tumor patients (e.g., breast, lung, and liver cancer) from the normal individuals. These advantages signify the promise of this miRNA sensor as a versatile tool in precision diagnosis.
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Affiliation(s)
- Tongtong Guo
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, School of Pharmacy, Guangxi Medical University, Nanning 530021, China
| | - Yuanhang Xiang
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, School of Pharmacy, Guangxi Medical University, Nanning 530021, China
- Center for Translational Medicine, Guangxi Beibu Gulf Marine Biomedicine Precision Development and High-Value Utilization Engineering Research Center, Guangxi Health Commission Key Laboratory of Basic Research on Antigeriatric Drugs, National Center for International Research of Bio-targeting Theranostics, Guangxi Medical University, Nanning 530021, China
| | - Hao Lu
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, School of Pharmacy, Guangxi Medical University, Nanning 530021, China
- Center for Translational Medicine, Guangxi Beibu Gulf Marine Biomedicine Precision Development and High-Value Utilization Engineering Research Center, Guangxi Health Commission Key Laboratory of Basic Research on Antigeriatric Drugs, National Center for International Research of Bio-targeting Theranostics, Guangxi Medical University, Nanning 530021, China
| | - Minmin Huang
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, School of Pharmacy, Guangxi Medical University, Nanning 530021, China
- Center for Translational Medicine, Guangxi Beibu Gulf Marine Biomedicine Precision Development and High-Value Utilization Engineering Research Center, Guangxi Health Commission Key Laboratory of Basic Research on Antigeriatric Drugs, National Center for International Research of Bio-targeting Theranostics, Guangxi Medical University, Nanning 530021, China
| | - Fengfei Liu
- Department of Clinical Laboratory, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, China
| | - Min Fang
- Department of Clinical Laboratory, The Affiliated Tumor Hospital of Guangxi Medical University, Nanning 530021, China
| | - Jia Liu
- Guangxi Key Laboratory of Basic and Translational Research of Bone and Joint Degenerative Diseases, Department of Orthopedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Yujin Tang
- Guangxi Key Laboratory of Basic and Translational Research of Bone and Joint Degenerative Diseases, Department of Orthopedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise 533000, China
| | - Xinchun Li
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, School of Pharmacy, Guangxi Medical University, Nanning 530021, China
| | - Fan Yang
- Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, School of Pharmacy, Guangxi Medical University, Nanning 530021, China
- Center for Translational Medicine, Guangxi Beibu Gulf Marine Biomedicine Precision Development and High-Value Utilization Engineering Research Center, Guangxi Health Commission Key Laboratory of Basic Research on Antigeriatric Drugs, National Center for International Research of Bio-targeting Theranostics, Guangxi Medical University, Nanning 530021, China
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Wang B, Wu HH, Abuetabh Y, Leng S, Davidge ST, Flores ER, Eisenstat DD, Leng R. p63, a key regulator of Ago2, links to the microRNA-144 cluster. Cell Death Dis 2022; 13:397. [PMID: 35459267 PMCID: PMC9033807 DOI: 10.1038/s41419-022-04854-1] [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: 09/09/2021] [Revised: 03/02/2022] [Accepted: 04/12/2022] [Indexed: 11/30/2022]
Abstract
Abstract As a key component of the RNA-induced silencing complex (RISC), Argonaute2 (Ago2) exhibits a dual function regulatory role in tumor progression. However, the mechanistic basis of differential regulation remains elusive. p63 is a homolog of the tumor suppressor p53. p63 isoforms play a critical role in tumorigenesis and metastasis. Herein, we show that p63 isoforms physically interact with and stabilize Ago2. Expression of p63 isoforms increases the levels of Ago2 protein, while depletion of p63 isoforms by shRNA decreases Ago2 protein levels. p63 strongly guides Ago2 dual functions in vitro and in vivo. Ectopic expression of the miR-144/451 cluster increases p63 protein levels; TAp63 transactivates the miR-144/451 cluster, forming a positive feedback loop. Notably, miR-144 activates p63 by directly targeting Itch, an E3 ligase of p63. Ectopic expression of miR-144 induces apoptosis in H1299 cells. miR-144 enhances TAp63 tumor suppressor function and inhibits cell invasion. Our findings uncover a novel function of p63 linking the miRNA-144 cluster and the Ago2 pathway. Facts and questions
Identification of Ago2 as a p63 target. Ago2 exhibits a dual function regulatory role in tumor progression; however, the molecular mechanism of Ago2 regulation remains unknown. p63 strongly guides Ago2 dual functions in vitro and in vivo. Unraveling a novel function of p63 links the miRNA-144 cluster and the Ago2 pathway.
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Affiliation(s)
- Benfan Wang
- Department of Laboratory Medicine and Pathology, 370 Heritage Medical Research Center, University of Alberta, Edmonton, AB, T6G 2S2, Canada
| | - H Helena Wu
- Department of Laboratory Medicine and Pathology, 370 Heritage Medical Research Center, University of Alberta, Edmonton, AB, T6G 2S2, Canada
| | - Yasser Abuetabh
- Department of Laboratory Medicine and Pathology, 370 Heritage Medical Research Center, University of Alberta, Edmonton, AB, T6G 2S2, Canada
| | - Sarah Leng
- Department of Laboratory Medicine and Pathology, 370 Heritage Medical Research Center, University of Alberta, Edmonton, AB, T6G 2S2, Canada
| | - Sandra T Davidge
- Department of Obstetrics & Gynecology & Physiology, 232 Heritage Medical Research Center, University of Alberta, Edmonton, AB, T6G 2S2, Canada
| | - Elsa R Flores
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA
| | - David D Eisenstat
- Department of Oncology, Cross Cancer Institute, 11560 University Ave., University of Alberta, Edmonton, AB, T6G 1Z2, Canada.,Department of Pediatrics, University of Alberta, 11405 - 87 Ave., Edmonton, AB, T6G 1C9, Canada.,Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, 50 Flemington Road, Parkville, VIC, 3052, Australia
| | - Roger Leng
- Department of Laboratory Medicine and Pathology, 370 Heritage Medical Research Center, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
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Jiang Y, Xu X, Xiao L, Wang L, Qiang S. The Role of microRNA in the Inflammatory Response of Wound Healing. Front Immunol 2022; 13:852419. [PMID: 35386721 PMCID: PMC8977525 DOI: 10.3389/fimmu.2022.852419] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 03/02/2022] [Indexed: 12/20/2022] Open
Abstract
Wound healing, a highly complex pathophysiological response to injury, includes four overlapping phases of hemostasis, inflammation, proliferation, and remodeling. Initiation and resolution of the inflammatory response are the primary requirements for wound healing, and are also key events that determines wound quality and healing time. Currently, the number of patients with persistent chronic wounds has generally increased, which imposes health and economic burden on patients and society. Recent studies have found that microRNA(miRNA) plays an essential role in the inflammation involved in wound healing and may provide a new therapeutic direction for wound treatment. Therefore, this review focused on the role and significance of miRNA in the inflammation phase of wound healing.
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Affiliation(s)
- Yuanyuan Jiang
- Center Laboratory, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
| | - Xiang Xu
- Center Laboratory, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
| | - Long Xiao
- Center Laboratory, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
| | - Lihong Wang
- Center Laboratory, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
| | - Sheng Qiang
- Center Laboratory, Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, China
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33
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Li C, Li R, Hu X, Zhou G, Jiang G. Tumor-promoting mechanisms of macrophage-derived extracellular vesicles-enclosed microRNA-660 in breast cancer progression. Breast Cancer Res Treat 2022; 192:353-368. [PMID: 35084622 DOI: 10.1007/s10549-021-06433-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 10/25/2021] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Breast cancer metastasis is the main cause of cancer-related death in women worldwide. Current therapies have remarkably improved the prognosis of breast cancer patients but still fail to manage metastatic breast cancer. Here, the present study was set to explore the role of microRNA (miR)-660 from tumor-associated macrophages (TAMs) in breast cancer, particularly in metastasis. MATERIALS AND METHODS We collected breast cancer tissues and isolated their polarized macrophages as well as extracellular vesicles (EVs), in which we measured the expression of miR-660, Kelch-like Protein 21 (KLHL21), and nuclear factor-κB (NF-κB) p65. Breast cancer cells were transfected with miR-660 mimic, miR-660 inhibitor, and sh-KLHL21 and then the cells were co-cultured with EVs or TAMs followed by detection of invasion and migration. Finally, mouse model of breast cancer was established to detect the effect of miR-660 or KLHL21 on metastasis by measuring the lymph node metastasis (LNM) foci in femur and lung. RESULTS KLHL21 was poorly expressed, whereas miR-660 was highly expressed in breast cancer tissues and cells. Of note, low KLHL21 expression or high miR-660 expression was related to poor overall survival. EVs-contained miR-660 was identified to bind to KLHL21, reducing the binding between KLHL21 and inhibitor kappa B kinase β (IKKβ) to activate the NF-κB p65 signaling pathway. Interestingly, EV-loaded miR-660 from TAMs could be internalized by breast cancer cells. Moreover, silencing of KLHL21 increased the number of lung LNM foci in vivo, while EVs-contained miR-660 promoted cancerous cell invasion and migration. DISCUSSION Taken altogether, our work shows that TAMs-EVs-shuttled miR-660 promotes breast cancer progression through KLHL21-mediated IKKβ/NF-κB p65 axis.
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Affiliation(s)
- Changchun Li
- Department of Thyroid and Breast Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215000, Jiangsu Province, People's Republic of China
| | - Ruiqing Li
- Department of Thyroid and Breast Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou, 225000, People's Republic of China
| | - Xingchi Hu
- Department of Thyroid and Breast Surgery, Yancheng City No. 1 People's Hospital, Yancheng, 224001, People's Republic of China
| | - Guangjun Zhou
- Department of Thyroid and Breast Surgery, Yancheng City No. 1 People's Hospital, Yancheng, 224001, People's Republic of China
| | - Guoqing Jiang
- Department of Thyroid and Breast Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, Sanxiang Road, Suzhou, 215000, Jiangsu Province, People's Republic of China.
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Alwhaibi A, Parvathagiri V, Verma A, Artham S, Adil MS, Somanath PR. Regulation of Let-7a-5p and miR-199a-5p Expression by Akt1 Modulates Prostate Cancer Epithelial-to-Mesenchymal Transition via the Transforming Growth Factor-β Pathway. Cancers (Basel) 2022; 14:cancers14071625. [PMID: 35406397 PMCID: PMC8996869 DOI: 10.3390/cancers14071625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/07/2022] [Accepted: 03/21/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary The molecular mechanisms regulating the switch from the growth of tumor cells to invasive phenotype for metastasis is largely unknown. Molecules such as Akt1 and TGFβ have been demonstrated to play reciprocal roles in the early and advanced stages of cancers, and epithelial-to-mesenchymal transition has been identified as a common link in the process. Advancing our knowledge on the direct association between these two pathways and how their effects are reconciled in the advanced stages of cancers such as prostate cancer will have therapeutic benefits. Identifying the role of microRNAs in the process will also benefit the scientific community. Abstract Akt1 suppression in advanced cancers has been indicated to promote metastasis. Our understanding of how Akt1 orchestrates this is incomplete. Using the NanoString®-based miRNA and mRNA profiling of PC3 and DU145 cells, and subsequent data analysis using the DIANA-mirPath, dbEMT, nCounter, and Ingenuity® databases, we identified the miRNAs and associated genes responsible for Akt1-mediated prostate cancer (PCa) epithelial-to-mesenchymal transition (EMT). Akt1 loss in PC3 and DU145 cells primarily induced changes in the miRNAs and mRNAs regulating EMT genes. These include increased miR-199a-5p and decreased let-7a-5p expression associated with increased TGFβ-R1 expression. Treatment with locked nucleic acid (LNA) miR-199a-5p inhibitor and/or let-7a-5p mimic induced expression changes in EMT genes correlating to their anticipated effects on PC3 and DU145 cell motility, invasion, and TGFβ-R1 expression. A correlation between increased miR-199a-5p and TGFβ-R1 expression with reduced let-7a-5p was also observed in high Gleason score PCa patients in the cBioportal database analysis. Collectively, our studies show the effect of Akt1 suppression in advanced PCa on EMT modulating miRNA and mRNA expression changes and highlight the potential benefits of miR-199a-5p and let-7a-5p in therapy and/or early screening of mPCa.
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Affiliation(s)
- Abdulrahman Alwhaibi
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA 30912, USA; (A.A.); (V.P.); (A.V.); (S.A.); (M.S.A.)
- Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
- Clinical Pharmacy Department, College of Pharmacy at King Saud University, Riyadh 11451, Saudi Arabia
| | - Varun Parvathagiri
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA 30912, USA; (A.A.); (V.P.); (A.V.); (S.A.); (M.S.A.)
- Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Arti Verma
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA 30912, USA; (A.A.); (V.P.); (A.V.); (S.A.); (M.S.A.)
- Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Sandeep Artham
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA 30912, USA; (A.A.); (V.P.); (A.V.); (S.A.); (M.S.A.)
- Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Mir S. Adil
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA 30912, USA; (A.A.); (V.P.); (A.V.); (S.A.); (M.S.A.)
- Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
| | - Payaningal R. Somanath
- Clinical and Experimental Therapeutics, University of Georgia, Augusta, GA 30912, USA; (A.A.); (V.P.); (A.V.); (S.A.); (M.S.A.)
- Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
- Vascular Biology Center, Augusta University, Augusta, GA 30912, USA
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
- Correspondence:
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Liu Y, Li B, Wang YJ, Fan Z, Du Y, Li B, Liu YJ, Liu B. In Situ Single-Molecule Imaging of MicroRNAs in Switchable Migrating Cells under Biomimetic Confinement. Anal Chem 2022; 94:4030-4038. [PMID: 35213802 DOI: 10.1021/acs.analchem.1c05223] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Spatial imaging of RNAs in single cells is extremely charming for deciphering of regulatory mechanisms in multiple migration modes during tumor metastasis. Herein, enzyme-free-mediated cascade amplified nanoprobes were designed for in situ single-molecule imaging of dual-microRNAs (miRNAs) in switchable migrating cells. Differential expression and localization of dual-miRNAs were clearly exhibited in multiple cell lines attributed to enhanced sensitivity via the cascade signal amplification strategy. Significantly, in situ three-dimensional (3D) imaging of dual-miRNAs in transition of cell migration phenotypes was successfully reconstructed in both non-confined and confined microenvironments in vitro, of which differential spatial distribution was observed in a single cell. This is very promising for exploring key roles of spatial RNA distribution in migrating cells at the single-molecule level, which will advance revealing the molecular mechanism and physical principle in 3D cell migration in vivo.
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Affiliation(s)
- Yixin Liu
- Department of Chemistry, Shanghai Stomatological Hospital, State Key Lab of Molecular Engineering of Polymers, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences Fudan University, Shanghai 200433, China
| | - Binxiao Li
- Department of Chemistry, Shanghai Stomatological Hospital, State Key Lab of Molecular Engineering of Polymers, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences Fudan University, Shanghai 200433, China
| | - Ya-Jun Wang
- Department of Chemistry, Shanghai Stomatological Hospital, State Key Lab of Molecular Engineering of Polymers, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences Fudan University, Shanghai 200433, China
| | - Zihui Fan
- Department of Chemistry, Shanghai Stomatological Hospital, State Key Lab of Molecular Engineering of Polymers, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences Fudan University, Shanghai 200433, China
| | - Yang Du
- Department of Chemistry, Shanghai Stomatological Hospital, State Key Lab of Molecular Engineering of Polymers, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences Fudan University, Shanghai 200433, China
| | - Bin Li
- Department of Chemistry, Shanghai Stomatological Hospital, State Key Lab of Molecular Engineering of Polymers, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences Fudan University, Shanghai 200433, China
| | - Yan-Jun Liu
- Department of Chemistry, Shanghai Stomatological Hospital, State Key Lab of Molecular Engineering of Polymers, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences Fudan University, Shanghai 200433, China
| | - Baohong Liu
- Department of Chemistry, Shanghai Stomatological Hospital, State Key Lab of Molecular Engineering of Polymers, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences Fudan University, Shanghai 200433, China
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Sun Y, Wang P, Zhang Q, Wu H. CDK14/β-catenin/TCF4/miR-26b positive feedback regulation modulating pancreatic cancer cell phenotypes in vitro and tumor growth in mice model in vivo. J Gene Med 2022; 24:e3343. [PMID: 33871149 DOI: 10.1002/jgm.3343] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Revised: 03/09/2021] [Accepted: 03/24/2021] [Indexed: 11/06/2022] Open
Abstract
INTRODUCTION Chemotherapy and radiotherapy have been reported to be basically ineffective for pancreatic ductal adenocarcinoma patients; thus, gene therapy might provide a novel approach. CDK14, a new oncogenic member of the CDK family involved in the pancreatic cancer cell response to gemcitabine treatment, has been reported to be regulated by microRNAs. In the present study, we aimed to investigate whether miR-26b regulated CDK14 expression to affect the phenotype of pancreatic cancer cells. METHODS Overexpression or knockdown of CDK14 or miR-26b was generated in pancreatic cancer cell lines and the function of CDK14 and miR-26b on cell phenotype and the Wnt signaling pathway was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-ethynyl-2'-deoxyuridine and transwell assays, as well as a xenograft model and western blotting. The predicted binding site between the 3'-untranslated region of CDK14 and miR-26b, miR-26b promoter and TCF4 was verified by luciferase or chromatin immunoprecipitation assays. RESULTS CDK14 overexpression inhibited p-GSK3β, whereas it promoted p-LRP6, the nuclear translocation of β-catenin and the transactivation of TCF4 transcription factor, thus promoting pancreatic cancer cell aggressiveness. miR-26b directly targeted CDK14 and inhibited CDK14 expression. In vitro and in vivo, miR-26b overexpression inhibited, and CDK14 overexpression promoted, cancer cell aggressiveness; CDK14 overexpression partially attenuated the miR-26b overexpression effects on cancer cells. The effects of miR-26b overexpression on tumor growth and the Wnt/β-catenin/TCF4 signaling were partially reversed by CDK14 overexpression. TCF4 inhibited the expression of miR-26b by targeting its promoter region. CONCLUSIONS CDK14, β-catenin, TCF4 and miR-26b form a positive feedback regulation for modulating pancreatic cancer cell phenotypes in vitro and tumor growth in vivo.
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Affiliation(s)
- Yunpeng Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Pengfei Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qiyu Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Huanhuan Wu
- Department of Post-anesthetic ICU, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Cao Y, Wang Z, Yan Y, Ji L, He J, Xuan B, Shen C, Ma Y, Jiang S, Ma D, Tong T, Zhang X, Gao Z, Zhu X, Fang JY, Chen H, Hong J. Enterotoxigenic Bacteroidesfragilis Promotes Intestinal Inflammation and Malignancy by Inhibiting Exosome-Packaged miR-149-3p. Gastroenterology 2021; 161:1552-1566.e12. [PMID: 34371001 DOI: 10.1053/j.gastro.2021.08.003] [Citation(s) in RCA: 150] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 07/20/2021] [Accepted: 08/02/2021] [Indexed: 01/08/2023]
Abstract
BACKGROUND & AIMS Enterotoxigenic Bacteroides fragilis (ETBF) is strongly associated with the occurrence of inflammatory bowel disease (IBD), colitis-associated colorectal cancer, and colorectal cancer (CRC). However, the mechanism of ETBF-induced intestinal inflammation and tumorigenesis remains unclear. METHODS microRNA sequencing was used to detect the differentially expressed microRNAs in both ETBF-treated cells and exosomes derived from ETBF-inoculated cells. Cell Counting Kit 8 assays were used to evaluate the effect of ETBF and exosomes on CRC cell proliferation. The biological role and mechanism of ETBF-mediated miR-149-3p in colitis and colon carcinogenesis were determined both in vitro and in vivo. RESULTS ETBF promoted CRC cell proliferation by down-regulating miR-149-3p both in vitro and in vivo. ETBF-down-regulated miR-149-3p depended on METTL14-mediated N6-methyladenosine methylation. As the target gene of miR-149-3p, PHF5A transactivated SOD2 through regulating KAT2A messenger RNA alternative splicing after ETBF treatment in CRC cells. miR-149-3p could be released in exosomes and mediated intercellular communication by modulating T-helper type 17 cell differentiation. The level of plasma exosomal miR-149-3p was gradually decreased from healthy control individuals to patients with IBD and CRC. miR-149-3p, existing in plasma exosomes, negatively correlated with the abundance of ETBF in patients with IBD and CRC. CONCLUSIONS Exosomal miR-149-3p derived from ETBF-treated cells facilitated T-helper type 17 cell differentiation. ETBF-induced colorectal carcinogenesis depended on down-regulating miR-149-3p and further promoting PHF5A-mediated RNA alternative splicing of KAT2A in CRC cells. Targeting the ETBF/miR-149-3p pathway presents a promising approach to treat patients with intestinal inflammation and CRC with a high amount of ETBF.
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MESH Headings
- Animals
- Bacteroides fragilis/pathogenicity
- Cell Differentiation
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/microbiology
- Colitis, Ulcerative/pathology
- Colon/metabolism
- Colon/microbiology
- Colon/pathology
- Colorectal Neoplasms/genetics
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/microbiology
- Colorectal Neoplasms/pathology
- Crohn Disease/genetics
- Crohn Disease/metabolism
- Crohn Disease/microbiology
- Crohn Disease/pathology
- Disease Models, Animal
- Exosomes/genetics
- Exosomes/metabolism
- Exosomes/microbiology
- HCT116 Cells
- Histone Acetyltransferases/genetics
- Histone Acetyltransferases/metabolism
- Host-Pathogen Interactions
- Humans
- Methyltransferases/genetics
- Methyltransferases/metabolism
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Nude
- MicroRNAs/genetics
- MicroRNAs/metabolism
- RNA-Binding Proteins/genetics
- RNA-Binding Proteins/metabolism
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Trans-Activators/genetics
- Trans-Activators/metabolism
- Mice
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Affiliation(s)
- Yingying Cao
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhenhua Wang
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuqing Yan
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Linhua Ji
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie He
- Department of Gastroenterology and Guangzhou Key Laboratory of Digestive Disease, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Baoqin Xuan
- State Key Laboratory for Oncogenes and Related Genes; Shanghai Cancer Institute; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chaoqin Shen
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yanru Ma
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shanshan Jiang
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dan Ma
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tianying Tong
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xinyu Zhang
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ziyun Gao
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoqiang Zhu
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jing-Yuan Fang
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haoyan Chen
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Jie Hong
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology and Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Fang JS, Hultgren NW, Hughes CCW. Regulation of Partial and Reversible Endothelial-to-Mesenchymal Transition in Angiogenesis. Front Cell Dev Biol 2021; 9:702021. [PMID: 34692672 PMCID: PMC8529039 DOI: 10.3389/fcell.2021.702021] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 06/22/2021] [Indexed: 12/11/2022] Open
Abstract
During development and in several diseases, endothelial cells (EC) can undergo complete endothelial-to-mesenchymal transition (EndoMT or EndMT) to generate endothelial-derived mesenchymal cells. Emerging evidence suggests that ECs can also undergo a partial EndoMT to generate cells with intermediate endothelial- and mesenchymal-character. This partial EndoMT event is transient, reversible, and supports both developmental and pathological angiogenesis. Here, we discuss possible regulatory mechanisms that may control the EndoMT program to dictate whether cells undergo complete or partial mesenchymal transition, and we further consider how these pathways might be targeted therapeutically in cancer.
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Affiliation(s)
- Jennifer S. Fang
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States
| | - Nan W. Hultgren
- Department of Ophthalmology, Stein Eye Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
| | - Christopher C. W. Hughes
- Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States
- Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, United States
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Escuin D, López-Vilaró L, Mora J, Bell O, Moral A, Pérez I, Arqueros C, García-Valdecasas B, Ramón Y Cajal T, Lerma E, Barnadas A. Circulating microRNAs in Early Breast Cancer Patients and Its Association With Lymph Node Metastases. Front Oncol 2021; 11:627811. [PMID: 34513655 PMCID: PMC8428362 DOI: 10.3389/fonc.2021.627811] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 08/04/2021] [Indexed: 12/13/2022] Open
Abstract
MicroRNAs have emerged as important regulators of the metastatic process. In addition, circulating miRNAs appear to be surprisingly stable in peripheral blood making them ideal noninvasive biomarkers for disease diagnosis. Here, we performed a proof-of-principle study to investigate the expression profile of circulating miRNAs and their association with the metastatic lymph node status in early breast cancer patients. Sentinel lymph node status was detected by one-step nucleic acid (OSNA) analysis. We performed RNA-sequencing in 16 plasma samples and validated the results by qPCR. Gene Ontology term enrichment and KEGG pathway analyses were carried out using DAVID tools. We found16 differentially expressed miRNAs (q < 0.01) in patients with positive SLNs. Fourteen miRNAs were down-regulated (miR-339-5p, miR-133a-3p, miR-326, miR-331-3p, miR-369-3p, miR-328-3p, miR-26a-3p, miR-139-3p, miR-493-3p, miR-664a-5p, miR-146a-5p, miR-323b-3p, miR-1307-3p and miR-423-3p) and 2 were up-regulated (miR-101-3pand miR-144-3p). Hierarchical clustering using differentially expressed miRNAs clearly distinguished patients according to their lymph node status. Gene ontology analysis showed a significant enrichment of biological processes associated with the regulation of the epithelial mesenchymal transition, cell proliferation and transcriptional regulation. Our results suggest the potential role of several circulating miRNAs as surrogate markers of lymph node metastases in early breast cancer patients. Further validation in a larger cohort of patients will be necessary to confirm our results.
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Affiliation(s)
- Daniel Escuin
- Clinical Oncology Research Group, Institut d'Investigacions Biomédiques Sant Pau (IIB-Sant Pau), Barcelona, Spain
| | - Laura López-Vilaró
- Clinical Oncology Research Group, Institut d'Investigacions Biomédiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Josefina Mora
- Department of Clinical Biochemistry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Olga Bell
- Clinical Oncology Research Group, Institut d'Investigacions Biomédiques Sant Pau (IIB-Sant Pau), Barcelona, Spain
| | - Antonio Moral
- Department of General Surgery, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,School of Medicine, Universitat Autónoma de Barcelona (UAB), Cerdanyola del Vallès, Spain
| | - Ignacio Pérez
- Department of General Surgery, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Cristina Arqueros
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Teresa Ramón Y Cajal
- Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Enrique Lerma
- Clinical Oncology Research Group, Institut d'Investigacions Biomédiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,School of Medicine, Universitat Autónoma de Barcelona (UAB), Cerdanyola del Vallès, Spain
| | - Agustí Barnadas
- Clinical Oncology Research Group, Institut d'Investigacions Biomédiques Sant Pau (IIB-Sant Pau), Barcelona, Spain.,School of Medicine, Universitat Autónoma de Barcelona (UAB), Cerdanyola del Vallès, Spain.,Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.,Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain
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Zhao M, Tang Z, Wang Y, Ding J, Guo Y, Gao T. A direct negative feedback loop of miR-4721/FOXA1/Nanog promotes nasopharyngeal cell stem cell enrichment and metastasis. J Transl Med 2021; 19:387. [PMID: 34503528 PMCID: PMC8428129 DOI: 10.1186/s12967-021-03059-y] [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: 02/22/2021] [Accepted: 08/27/2021] [Indexed: 11/10/2022] Open
Abstract
Objective The recurrence and metastasis of nasopharyngeal cancer (NPC) may be mainly attributed to the persistence of cancer stem cells (CSCs); however, the linkage mechanism has yet to be fully elucidated. Methods The levels of miR-4721, FOXA1, and Nanog expression in NPC were detected by in situ hybridization and immunohistochemistry. In vivo and in vitro metastasis assays confirmed miR-4721 promotes cell migration and invasion. Tumor spheroid formation assay, side population (SP) assay, and ALDEFLUOR assay verified miR-4721 regulates cancer stem cell-like properties. Luciferase reporter assay showed that miR-4721 directly regulates FOXA1 and FOXA1 effects the promoter activity of miR-4721 and Nanog. Chromatin immunoprecipitation (ChIP) analysis and electrophoresis mobility shift assay (EMSA) revealed that FOXA1 combined the promoter region of human miR-4721 and Nanog and the possible mechanism was also analyzed. Results In this study, a new mechanism of NPC tumorigenesis related to miR-4721 was verified. We found that miR-4721, FOXA1 and Nanog control their expressions through a negative feedback loop and then activate the downstream regulator of stem cell signaling to promote the enrichment and metastasis of NPC stem cells. Conclusion These findings elucidate that the feedback loop of miR-4721/FOXA1/Nanog can regulate stemness and metastasis in NPC and may provide an experimental theoretical basis for metastasis and treatment resistance in NPC. Supplementary Information The online version contains supplementary material available at 10.1186/s12967-021-03059-y.
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Affiliation(s)
- Mengyang Zhao
- Department of Oncology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, China.
| | - Zibo Tang
- Cancer Center, Traditional Chinese Medicine-Integrated Hospital of Southern Medical University, Guangzhou, 510000, China
| | - Yijun Wang
- Department of Oncology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, China
| | - Jiaojiao Ding
- Department of Oncology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, China
| | - Ying Guo
- Department of Oncology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, China
| | - Tianhui Gao
- Department of Oncology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, 450003, Henan, China
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Li Z, Zhu Z, Wang Y, Wang Y, Li W, Wang Z, Zhou X, Bao Y. hsa‑miR‑15a‑5p inhibits colon cell carcinoma via targeting CCND1. Mol Med Rep 2021; 24:735. [PMID: 34414457 PMCID: PMC8404101 DOI: 10.3892/mmr.2021.12375] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 02/09/2021] [Indexed: 12/24/2022] Open
Abstract
Colon carcinoma is one of the most common cancers worldwide. Epidemiological studies have revealed that colon cancer is the third leading cause of cancer-related deaths, which is due to the increased incidence and mortality rates. However, the treatment strategies for colon cancer remain unsatisfactory for patients, especially for those with advanced or recurrent colon cancer. Dysregulated microRNAs (miRNAs) are considered to influence tumor development and metastasis. However, the molecular mechanism through which miRNAs affect cancer progression is not yet completely understood. The aim of the present study was to investigate the expression levels of has-miR-15a-5p and its molecular mechanism in colon cell carcinoma. In the present study, the expression levels of hsa-miR-15a-5p were found to be decreased in colon tumor tissues and cancer cell lines. Hsa-miR-15a-5p overexpression inhibited colon cell proliferation and migration. Mechanistically, the G1/S-specific cyclin-D1 (CCND1) gene was predicted as a target of hsa-miR-15a-5p, as evidenced by bioinformatics and dual-luciferase reporter assay analyses. CCND1 overexpression significantly increased the progression of colon cancer. Furthermore, CCND1 was demonstrated to mediate the effects of hsa-miR-15a-5p on colon cancer cells. The present study demonstrated that hsa-miR-15a-5p alleviated the proliferation, migration and invasion of colon cancer by targeting the CCND1 gene, which represents a potential molecular target for the diagnosis and treatment of colon cancer.
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Affiliation(s)
- Zhipeng Li
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Zeyu Zhu
- Department of Orthopedics, Huaian Hospital, Huaian, Jiangsu 223200, P.R. China
| | - Yanjun Wang
- Department of Women's Preventive Health, Huishan No. 2 People's Hospital, Wuxi, Jiangsu 214400, P.R. China
| | - Ying Wang
- Department of Radiotherapy, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Weibing Li
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Zhigang Wang
- Department of Hospital Quality Management, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
| | - Xinyuan Zhou
- Department of Gastroenterology, Wuxi Hospital of TCM, Affiliated to Nanjing University of Chinese Medicine, Wuxi, Jiangsu 214000, P.R. China
| | - Yuhua Bao
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China
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The Identification of HSA-MIR-17-5P Existence in the Exosome of Adipose-Derived Stem Cells and Adipocytes. JOURNAL OF BIOMIMETICS BIOMATERIALS AND BIOMEDICAL ENGINEERING 2021. [DOI: 10.4028/www.scientific.net/jbbbe.52.66] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
MicroRNAs (miRNAs) have ability to down-regulate gene expressions. hsa-miR-17-5p, has been confirmed as an oncogene or tumor suppressor. However, the existence on human adipose-derived stem cells (ADSCs) or adipocytes, is still unclear. Many researchers emphasizing the role of hsa-miR-17-5p on cellular senescence, aging and cancer, but not specific on the expression in the exosome of human ADSCs and adipocytes. The primary ADSCs were derived from subcutaneous adipose tissue of pregnant woman during elective cesarean operation, then processed by combining conventional and enzymatic methods. Adipocytes were differentiated by using the StemPro Adipogenesis Differentiation kit® and Oil Red-O staining. Exosomes were isolated using Exosome Purification and RNA Isolation kit® and were characterized by scanning electron microscope. The markers, CD34 and CD44, were identified and analyzed by using FACS analysis. Subsequently, microRNA was extracted and observed for hsa-miR-17-5p expression. This study showed that ADSCs and adipocytes were proved to express CD34+ and CD44+. The hsa-miR-17-5p were also detected in both the exosome of ADSCs and adipocytes. Although the source of the ADSCs was from pregnant woman, the characteristic was similar with the ones from non-pregnant woman. Our study also supports the questionable existence of CD34 in ADSCs. Having confirmed the characteristics, we proved that the exosomes of ADSCs and adipocytes expressed similar hsa-miR-17-5p despite they are from phenotypically different cell types and may have distinct roles. However, further research steps should be done in the future to verify the role of hsa-miR-17-5p towards senescent cell and ADSC differentiation.
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Guo W, Wang S, Zhang X, Shi M, Duan F, Hao J, Gu K, Quan L, Wu Y, Liang Z, Wang Y. Acidic pH transiently prevents the silencing of self-renewal and dampens microRNA function in embryonic stem cells. Sci Bull (Beijing) 2021; 66:1319-1329. [PMID: 36654154 DOI: 10.1016/j.scib.2021.03.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/18/2020] [Accepted: 11/02/2020] [Indexed: 02/07/2023]
Abstract
Enhanced glycolysis is a distinct feature associated with numerous stem cells and cancer cells. However, little is known about its regulatory roles in gene expression and cell fate determination. Here, we confirm that glycolytic metabolism and lactate production decrease during the differentiation of mouse embryonic stem cells (mESCs). Importantly, acidic pH due to lactate accumulation can transiently prevent the silencing of mESC self-renewal in differentiation conditions. Furthermore, acidic pH partially blocks the differentiation of human ESCs (hESCs). Mechanistically, acidic pH downregulates AGO1 protein and de-represses a subset of mRNA targets of miR-290/302 family of microRNAs which facilitate the exit of naive pluripotency state in mESCs. Interestingly, AGO1 protein is also downregulated by acidic pH in cancer cells. Altogether, this study provides insights into the potential function and underlying mechanism of acidic pH in pluripotent stem cells (PSCs).
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Affiliation(s)
- Wenting Guo
- Department of Medical Research Center, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
| | - Shaohua Wang
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Xiaoshan Zhang
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Ming Shi
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Feifei Duan
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Jing Hao
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Kaili Gu
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Li Quan
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Yixia Wu
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China
| | - Zhiyong Liang
- Department of Pathology, Molecular Pathology Research Centre, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yangming Wang
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, Peking University, Beijing 100871, China.
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Dräger O, Metz K, Busch M, Dünker N. Role of L1CAM in retinoblastoma tumorigenesis: identification of novel therapeutic targets. Mol Oncol 2021; 16:957-981. [PMID: 34228897 PMCID: PMC8847994 DOI: 10.1002/1878-0261.13054] [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: 03/11/2021] [Revised: 05/11/2021] [Accepted: 07/05/2021] [Indexed: 11/08/2022] Open
Abstract
The study presented focuses on the role of the neuronal cell adhesion molecule L1 cell adhesion molecule (L1CAM) in retinoblastoma (RB), the most common malignant intraocular childhood tumor. L1CAM is differentially expressed in a variety of human cancers and has been suggested as a promising therapeutic target. We likewise observed differential expression patterns for L1CAM in RB cell lines and patient samples. The two proteases involved in ectodomain shedding of L1CAM (L1CAM sheddases: ADAM10 and ADAM17) were likewise differentially expressed in the RB cell lines investigated, and an involvement in L1CAM processing in RB cells could be verified. We also identified ezrin, galectin-3, and fibroblast growth factor basic as L1CAM signaling target genes in RB cells. Lentiviral L1CAM knockdown induced apoptosis and reduced cell viability, proliferation, growth, and colony formation capacity of RB cells, whereas L1CAM-overexpressing RB cells displayed the opposite effects. Chicken chorioallantoic membrane assays revealed that L1CAM depletion decreases the tumorigenic and migration potential of RB cells in vivo. Moreover, L1CAM depletion decreased viability and tumor growth of etoposide-resistant RB cell lines upon etoposide treatment in vitro and in vivo. Thus, L1CAM and its processing sheddases are potential novel targets for future therapeutic RB approaches.
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Affiliation(s)
- Oliver Dräger
- Institute of Anatomy II, Department of Neuroanatomy, University of Duisburg-Essen, Medical Faculty, Germany
| | - Klaus Metz
- Institute of Pathology, University of Duisburg-Essen, Medical Faculty, Germany
| | - Maike Busch
- Institute of Anatomy II, Department of Neuroanatomy, University of Duisburg-Essen, Medical Faculty, Germany
| | - Nicole Dünker
- Institute of Anatomy II, Department of Neuroanatomy, University of Duisburg-Essen, Medical Faculty, Germany
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Li T, Tang C, Huang Z, Yang L, Dai H, Tang B, Xiao B, Li J, Lei X. miR-144-3p inhibited the growth, metastasis and epithelial-mesenchymal transition of colorectal adenocarcinoma by targeting ZEB1/2. Aging (Albany NY) 2021; 13:17349-17369. [PMID: 34226299 PMCID: PMC8312459 DOI: 10.18632/aging.203225] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 06/04/2021] [Indexed: 01/05/2023]
Abstract
miR-144-3p is aberrantly expressed in several types of human cancer and functions as a tumor suppressor by inhibiting metastasis. However, the clinical significance and biological function of miR-144-3p in colorectal adenocarcinoma (CRA) have yet to be elucidated. Here we reported that miR-144-3p expression level was significantly down-regulated in CRA tissues compared with matched noncancerous colorectal mucosae tissues. Low miR-144-3p expression was correlated with adverse clinicopathologic characteristics and poor prognosis of CRA patients. Cox regression analysis showed that low miR-144-3p expression was an independent risk factor for DFS and OS in CRA. In vitro and in vivo assays showed that miR-144-3p significantly inhibited proliferation, migration and invasion of CRA cells. In particular, miR-144-3p could suppress EMT process of CRA cells by regulating the cytoskeleton and EMT markers. Bioinformatics analysis indicated that EMT associated transcription factors ZEB1 and ZEB2 were potential targets of miR-144-3p, and miR-144-3p inhibited ZEB1 and ZEB2 expression and was negatively correlated with their expression in CRA. Finally, we confirmed that ZEB1 and ZEB2 down-regulation collaboratively mediated the inhibitory effect of miR-144-3p on proliferation, invasion and EMT of CRA cells. In conclusion, our study provided evidence that miR-144-3p could inhibit CRA cell proliferation, invasion and EMT by targeting ZEB1/2.
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Affiliation(s)
- Taiyuan Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang 330006, Jiangxi, China
| | - Cheng Tang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Zhixiang Huang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Lingling Yang
- Department of Gastroenterology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Hua Dai
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Bo Tang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Benping Xiao
- Department of General Surgery, Jiangxi Pingxiang People’s Hospital, Pingxiang 337000, Jiangxi, China
| | - Jianfeng Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
| | - Xiong Lei
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi, China
- Gastrointestinal Surgical Institute, Nanchang University, Nanchang 330006, Jiangxi, China
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Wang YL, Liang RH, Wang CY, Zhang RP, Wu SY, Han X, Zhang GL. MicroRNA-543 inhibits the proliferation, migration, invasion, and epithelial-mesenchymal transition of triple-negative breast cancer cells via down-regulation of ACTL6A gene. Clin Transl Oncol 2021; 24:84-92. [PMID: 34181232 DOI: 10.1007/s12094-021-02672-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 06/17/2021] [Indexed: 11/26/2022]
Abstract
PURPOSE To investigate the effect of microRNA-543 (miR-543) on the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of triple-negative breast cancer (TNBC) cells, and the associated mechanism. METHODS Human breast cancer cells (MDA-MB-231, HCC1937, and MCF-7, ZR-75-1) and normal human breast epithelial cell line (MCF10A) were transfected with miR-543 mimics or inhibitor using lipofectamine 2000. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting were used to determine the mRNA and protein expression levels of miR-543, actin-like protein 6A (ACTL6A), vimentin, Snail, and E-cadherin in breast cancer cells/tissue. Cell counting kit-8 (CCK-8), wound-healing, and Transwell assays were used to measure the effect of miR-543 on TNBC cell proliferation, invasion, and migration. Overall survival was determined using data from Gene Expression Omnibus (GEO) and Cancer Genome Atlas (TCGA) databases. Bioinformatics analysis and luciferase reporter gene assay were used to determine the regulatory effect of miR-543 on ACTL6A. RESULTS The level of expression of miR-543 was significantly lower in breast cancer cells/tissue than in normal human breast epithelial cell/tissue (p < 0.05). MicroRNA-543 expression level was significantly reduced in TNBC cells/tissue, relative to the other breast cancer cells/normal breast tissue (p < 0.05). MicroRNA-543 significantly suppressed tumor growth and the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of TNBC cells, in mouse xenograft model (p < 0.05). CONCLUSIONS miR-543 influences the biological behavior of TNBC cells by directly targeting ACTL6A gene. miR-543 could serve as a novel diagnostic and therapeutic target for TNBC.
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Affiliation(s)
- Y L Wang
- Department of Medical Oncology, Baotou Cancer Hospital, Baotou, 014030, Inner Mongolia, China
| | - R H Liang
- Department of Medical Oncology, Baotou Cancer Hospital, Baotou, 014030, Inner Mongolia, China
| | - C Y Wang
- Department of Medical Oncology, Baotou Cancer Hospital, Baotou, 014030, Inner Mongolia, China
| | - R P Zhang
- Department of Medical Oncology, Baotou Cancer Hospital, Baotou, 014030, Inner Mongolia, China
| | - S Y Wu
- Department of Medical Oncology, Baotou Cancer Hospital, Baotou, 014030, Inner Mongolia, China
| | - X Han
- Department of Breast Surgery, Baotou Cancer Hospital, No. 18 Tuanjie Street, Qingshan District, Baotou, 014030, Inner Mongolia, China
| | - G L Zhang
- Department of Breast Surgery, Baotou Cancer Hospital, No. 18 Tuanjie Street, Qingshan District, Baotou, 014030, Inner Mongolia, China.
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47
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Feng P, Ge Z, Guo Z, Lin L, Yu Q. A Comprehensive Analysis of the Downregulation of miRNA-1827 and Its Prognostic Significance by Targeting SPTBN2 and BCL2L1 in Ovarian Cancer. Front Mol Biosci 2021; 8:687576. [PMID: 34179092 PMCID: PMC8226272 DOI: 10.3389/fmolb.2021.687576] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/19/2021] [Indexed: 12/19/2022] Open
Abstract
Background: Previous studies demonstrated that miRNA-1827 could repress various cancers on proliferation, angiogenesis, and metastasis. However, little attention has been paid to its role in ovarian cancer as a novel biomarker or intervention target, especially its clinical significance and underlying regulatory network. Methods: A meta-analysis of six microarrays was adopted here to determine the expression trend of miRNA-1827, and was further validated by gene expression profile data and cellular experiments. We explored the functional annotations through enrichment analysis for the differentially expressed genes targeted by miRNA-1827. Subsequently, we identified two hub genes, SPTBN2 and BCL2L1, based on interaction analysis using two online archive tools, miRWALK (it consolidates the resources of 12 miRNA-focused servers) and Gene Expression Profiling Interactive Analysis (GEPIA). Finally, we validated their characteristics and clinical significance in ovarian cancer. Results: The comprehensive meta-analysis revealed that miRNA-1827 was markedly downregulated in clinical and cellular specimens. Transfection of the miRNA-1827 mimic could significantly inhibit cellular proliferation. Concerning its target genes, they were involved in diverse biological processes related to tumorigenesis, such as cell proliferation, migration, and the apoptosis signaling pathway. Moreover, interaction analysis proved that two hub genes, SPTBN2 and BCL2L1, were highly associated with poor prognosis in ovarian cancer. Conclusion: These integrated bioinformatic analyses indicated that miRNA-1827 was dramatically downregulated in ovarian cancer as a tumor suppressor. The upregulation of its downstream modulators, SPTBN2 and BCL2L1, was associated with an unfavorable prognosis. Thus, the present study has identified miRNA-1827 as a potential intervention target for ovarian cancer based on our bioinformatic analysis processes.
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Affiliation(s)
- Penghui Feng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhitong Ge
- Department of Ultrasound, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zaixin Guo
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin Lin
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of Obstetrics and Gynecology, The Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Beijing, China
| | - Qi Yu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Forbes TA, Brown BD, Lai C. Therapeutic RNA interference: A novel approach to the treatment of primary hyperoxaluria. Br J Clin Pharmacol 2021; 88:2525-2538. [PMID: 34022071 PMCID: PMC9291495 DOI: 10.1111/bcp.14925] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 04/19/2021] [Accepted: 05/08/2021] [Indexed: 12/13/2022] Open
Abstract
RNA interference (RNAi) is a natural biological pathway that inhibits gene expression by targeted degradation or translational inhibition of cytoplasmic mRNA by the RNA induced silencing complex. RNAi has long been exploited in laboratory research to study the biological consequences of the reduced expression of a gene of interest. More recently RNAi has been demonstrated as a therapeutic avenue for rare metabolic diseases. This review presents an overview of the cellular RNAi machinery as well as therapeutic RNAi design and delivery. As a clinical example we present primary hyperoxaluria, an ultrarare inherited disease of increased hepatic oxalate production which leads to recurrent calcium oxalate kidney stones. In the most common form of the disease (Type 1), end‐stage kidney disease occurs in childhood or young adulthood, often necessitating combined kidney and liver transplantation. In this context we discuss nedosiran (Dicerna Pharmaceuticals, Inc.) and lumasiran (Alnylam Pharmaceuticals), which are both novel RNAi therapies for primary hyperoxaluria that selectively reduce hepatic expression of lactate dehydrogenase and glycolate oxidase respectively, reducing hepatic oxalate production and urinary oxalate levels. Finally, we consider future optimizations advances in RNAi therapies.
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Affiliation(s)
- Thomas A Forbes
- Royal Children's Hospital, Parkville, Victoria, Australia.,Murdoch Children's Research Institute, Parkville, Victoria, Australia.,University of Melbourne, Parkville, Victoria, Australia
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Brand H, Barnabas GD, Sapoznik S, Bahar-Shany K, Pozniak Y, Yung Y, Hourvitz A, Geiger T, Jacob-Hirsch J, Levanon K. NF-κB-miR-155 axis activation mediates ovulation-induced oncogenic effects in fallopian tube epithelium. Carcinogenesis 2021; 41:1703-1712. [PMID: 32614381 DOI: 10.1093/carcin/bgaa068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 06/15/2020] [Accepted: 06/24/2020] [Indexed: 02/06/2023] Open
Abstract
The fallopian tube secretory epithelial cells (FTSECs) are the cell-of-origin of most high-grade serous ovarian carcinomas (HGSOC). FTSECs are repeatedly exposed to inflammation induced by follicular fluid (FF) that is released with every ovulation cycle throughout a woman's reproductive years. Uninterrupted ovulation cycles are an established risk factor for HGSOC. Stimuli present in the FF induce an inflammatory environment which may cause DNA damage eventually leading to serous tumorigenesis. With the aim of elucidating possible mechanistic pathways, we established an 'ex vivo persistent ovulation model' mimicking the repeated exposure of human benign fallopian tube epithelium (FTE) to FF. We performed mass spectrometry analysis of the secretome of the ex vivo cultures as well as confirmatory targeted expressional and functional analyses. We demonstrated activation of the NF-κB pathway and upregulation of miR-155 following short-term exposure of FTE to human FF. Increased expression of miR-155 was also detected in primary HGSOC tumors compared with benign primary human FTE and corresponded with changes in the expression of miR-155 target genes. The phenotype of miR-155 overexpression in FTSEC cell line is of increased migratory and altered adhesion capacities. Overall, activation of the NF-κB-miR-155 axis in FTE may represent a possible link between ovulation-induced inflammation, DNA damage, and transcriptional changes that may eventually lead to serious carcinogenesis.
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Affiliation(s)
- Hadar Brand
- Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel.,Sackler Faculty of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | - Georgina D Barnabas
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | - Stav Sapoznik
- Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Keren Bahar-Shany
- Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Yair Pozniak
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | - Yuval Yung
- IVF Unit and Reproduction Lab, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Ariel Hourvitz
- Sackler Faculty of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.,IVF Unit and Reproduction Lab, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, Ramat Gan, Israel
| | - Tamar Geiger
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
| | | | - Keren Levanon
- Sheba Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel.,Sackler Faculty of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel
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50
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Wu Y, Zhu B, Yan Y, Bai S, Kang H, Zhang J, Ma W, Gao Y, Hui B, Li R, Zhang X, Ren J. Long non-coding RNA SNHG1 stimulates ovarian cancer progression by modulating expression of miR-454 and ZEB1. Mol Oncol 2021; 15:1584-1596. [PMID: 33641229 PMCID: PMC8096788 DOI: 10.1002/1878-0261.12932] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/21/2020] [Accepted: 02/26/2021] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer (OC) is highly prevalent and is associated with high mortality rates due to metastasis and relapse. In this study, we assessed the role of long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) in OC to gain further insight into mechanisms that contribute to its aggressiveness. We analyzed the correlation between SNHG1, miR-454 and zinc finger E-box-binding homeobox 1 (ZEB1) using a dual-luciferase reporter assay. Alterations in cell metastasis and invasiveness were observed using wound-healing and Transwell invasion assays, respectively. Tumor xenografts allowed us to monitor liver metastasis of mice injected with A2780 cells. We found that SNHG1 is overexpressed in OC. Downregulation of SNHG1 promoted miR-454 expression and reduced ZEB1 levels. In addition, knockdown of SNHG1, also reduced the aggressiveness of A2780 and SK-OV3 cells. Furthermore, SNHG1 downregulation by siRNA hindered cell migration and invasion; however, this effect was reversed by co-transfection of miR-454 into A2780 and SK-OV3 cells. Moreover, SNHG1 increased ZEB1 expression by downregulating miR-454 and activated Akt signaling, thereby promoting epithelial-mesenchymal transition and enhancing the invasiveness of OC cells. Tumor xenograft analyses confirmed that SNHG1 affects OC proliferation and metastasis in vivo. In summary, our data demonstrate that SNHG1 plays crucial roles in tumor progression and may be a useful maker for OC prognosis.
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MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Ovarian Epithelial/genetics
- Carcinoma, Ovarian Epithelial/pathology
- Cell Line, Tumor
- Cell Proliferation/genetics
- Disease Progression
- Epithelial-Mesenchymal Transition/genetics
- Female
- Gene Expression Regulation, Neoplastic
- HEK293 Cells
- Humans
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/genetics
- Ovarian Neoplasms/genetics
- Ovarian Neoplasms/pathology
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/physiology
- Zinc Finger E-box-Binding Homeobox 1/genetics
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Affiliation(s)
- YinYing Wu
- Department of Chemotherapy, Oncology DepartmentFirst Affiliated Hospital of Xi’an Jiaotong UniversityChina
| | - Bo Zhu
- Department of Pulmonary and Critical Care MedicineFirst Affiliated Hospital of Xi’an Jiaotong UniversityChina
| | - Yanli Yan
- Department of Radiotherapy, Oncology DepartmentFirst Affiliated Hospital of Xi’an Jiaotong UniversityChina
| | - Shuheng Bai
- Department of Radiotherapy, Oncology DepartmentFirst Affiliated Hospital of Xi’an Jiaotong UniversityChina
| | - Haojing Kang
- Department of Radiotherapy, Oncology DepartmentFirst Affiliated Hospital of Xi’an Jiaotong UniversityChina
| | | | - Wen Ma
- Medical SchoolXi’an Jiaotong UniversityChina
| | - Ying Gao
- Department of Radiotherapy, Oncology DepartmentFirst Affiliated Hospital of Xi’an Jiaotong UniversityChina
| | - Beina Hui
- Department of Radiotherapy, Oncology DepartmentFirst Affiliated Hospital of Xi’an Jiaotong UniversityChina
| | - Rong Li
- Department of Radiotherapy, Oncology DepartmentFirst Affiliated Hospital of Xi’an Jiaotong UniversityChina
| | - Xiaozhi Zhang
- Department of Radiotherapy, Oncology DepartmentFirst Affiliated Hospital of Xi’an Jiaotong UniversityChina
| | - Juan Ren
- Department of Radiotherapy, Oncology DepartmentFirst Affiliated Hospital of Xi’an Jiaotong UniversityChina
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