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Plut S, Gavric A, Glavač D. Non-Coding RNAs as Potential Biomarkers for Colorectal Polyps and Cancer Detection. Int J Mol Sci 2025; 26:4106. [PMID: 40362348 PMCID: PMC12072050 DOI: 10.3390/ijms26094106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Revised: 04/09/2025] [Accepted: 04/22/2025] [Indexed: 05/15/2025] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The precursor of CRC is a colorectal polyp, of which adenoma is the most common histological type. The initial step in CRC development is the gradual accumulation of a series of genetic and epigenetic alterations in the normal colonic epithelium. Genetic alterations play a major role in a subset of CRCs, but the pathophysiological contribution of epigenetic aberrations has recently attracted attention. Epigenetic marks occur early in cancer pathogenesis and are therefore important molecular hallmarks of cancer. This makes some epigenetic alterations clinically relevant for early detection not only of CRC but also of precancerous polyps. In this review we focus on three types of non-coding RNAs as epigenetic regulators: miRNA, lncRNA, and lncRNAs, highlighting their biomarker potential.
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Affiliation(s)
- Samo Plut
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (S.P.); (A.G.)
- Ljubljana Digestive Endoscopy Research Group (LuDERG), Department of Gastroenterology, UMC Ljubljana, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Aleksandar Gavric
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (S.P.); (A.G.)
- Ljubljana Digestive Endoscopy Research Group (LuDERG), Department of Gastroenterology, UMC Ljubljana, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Damjan Glavač
- Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
- Center for Human Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia
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Senousy MA, Shaker OG, Ayeldeen G, Radwan AF. Association of lncRNA MEG3 rs941576 polymorphism, expression profile, and its related targets with the risk of obesity-related colorectal cancer: potential clinical insights. Sci Rep 2024; 14:10271. [PMID: 38704452 PMCID: PMC11069513 DOI: 10.1038/s41598-024-60265-6] [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: 02/09/2024] [Accepted: 04/21/2024] [Indexed: 05/06/2024] Open
Abstract
The identification of novel screening tools is imperative to empower the early detection of colorectal cancer (CRC). The influence of the long non-coding RNA maternally expressed gene 3 (MEG3) rs941576 single nucleotide polymorphism on CRC susceptibility remains uninvestigated. This research appraised MEG3 rs941576 association with the risk and clinical features of CRC and obesity-related CRC and its impact on serum MEG3 expression and its targets miR-27a/insulin-like growth factor 1 (IGF1)/IGF binding protein 3 (IGFBP3) and miR-181a/sirtuin 1 (SIRT1), along with the potential of these markers in obesity-related CRC diagnosis. 130 CRC patients (60 non-obese and 70 obese) and 120 cancer-free controls (64 non-obese and 56 obese) were enrolled. MEG3 targets were selected using bioinformatics analysis. MEG3 rs941576 was associated with magnified CRC risk in overall (OR (95% CI) 4.69(1.51-14.57), P = 0.0018) and stratified age and gender groups, but not with obesity-related CRC risk or MEG3/downstream targets' expression. Escalated miR-27a and IGFBP3 and reduced IGF1 serum levels were concomitant with MEG3 downregulation in overall CRC patients versus controls and obese versus non-obese CRC patients. Serum miR-181a and SIRT1 were upregulated in CRC patients versus controls but weren't altered in the obese versus non-obese comparison. Serum miR-181a and miR-27a were superior in overall and obesity-related CRC diagnosis, respectively; meanwhile, IGF1 was superior in distinguishing obese from non-obese CRC patients. Only serum miR-27a was associated with obesity-related CRC risk in multivariate logistic analysis. Among overall CRC patients, MEG3 rs941576 was associated with lymph node (LN) metastasis and tumor stage, serum MEG3 was negatively correlated with tumor stage, while SIRT1 was correlated with the anatomical site. Significant correlations were recorded between MEG3 and anatomical site, SIRT1 and tumor stage, and miR-27a/IGFBP3 and LN metastasis among obese CRC patients, while IGF1 was correlated with tumor stage and LN metastasis among non-obese CRC patients. Conclusively, this study advocates MEG3 rs941576 as a novel genetic marker of CRC susceptibility and prognosis. Our findings accentuate circulating MEG3/miR-27a/IGF1/IGFBP3, especially miR-27a as valuable markers for the early detection of obesity-related CRC. This axis along with SIRT1 could benefit obesity-related CRC prognosis.
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Affiliation(s)
- Mahmoud A Senousy
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
| | - Olfat G Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, 11562, Egypt
| | - Ghada Ayeldeen
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, 11562, Egypt
| | - Abdullah F Radwan
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Egyptian Russian University, Cairo, 11829, Egypt
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Davodabadi F, Mirinejad S, Malik S, Dhasmana A, Ulucan-Karnak F, Sargazi S, Sargazi S, Fathi-Karkan S, Rahdar A. Nanotherapeutic approaches for delivery of long non-coding RNAs: an updated review with emphasis on cancer. NANOSCALE 2024; 16:3881-3914. [PMID: 38353296 DOI: 10.1039/d3nr05656b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
The long noncoding RNAs (lncRNAs) comprise a wide range of RNA species whose length exceeds 200 nucleotides, which regulate the expression of genes and cellular functions in a wide range of organisms. Several diseases, including malignancy, have been associated with lncRNA dysregulation. Due to their functions in cancer development and progression, lncRNAs have emerged as promising biomarkers and therapeutic targets in cancer diagnosis and treatment. Several studies have investigated the anti-cancer properties of lncRNAs; however, only a few lncRNAs have been found to exhibit tumor suppressor properties. Furthermore, their length and poor stability make them difficult to synthesize. Thus, to overcome the instability of lncRNAs, poor specificity, and their off-target effects, researchers have constructed nanocarriers that encapsulate lncRNAs. Recently, translational medicine research has focused on delivering lncRNAs into tumor cells, including cancer cells, through nano-drug delivery systems in vivo. The developed nanocarriers can protect, target, and release lncRNAs under controlled conditions without appreciable adverse effects. To deliver lncRNAs to cancer cells, various nanocarriers, such as exosomes, microbubbles, polymer nanoparticles, 1,2-dioleyl-3-trimethylammoniumpropane chloride nanocarriers, and virus-like particles, have been successfully developed. Despite this, every nanocarrier has its own advantages and disadvantages when it comes to delivering nucleic acids effectively and safely. This article examines the current status of nanocarriers for lncRNA delivery in cancer therapy, focusing on their potential to enhance cancer treatment.
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Affiliation(s)
- Fatemeh Davodabadi
- Department of Biology, Faculty of Basic Science, Payame Noor University, Tehran, Iran.
| | - Shekoufeh Mirinejad
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Sumira Malik
- Amity Institute of Biotechnology, Amity University Jharkhand, Ranchi-834002, India.
| | - Archna Dhasmana
- Himalayan School of Biosciences, Swami Rama Himalayan University, Jolly Grant, Dehradun, Uttarakhand, 248140, India.
| | - Fulden Ulucan-Karnak
- Department of Medical Biochemistry, Institute of Health Sciences, Ege University, İzmir 35100, Turkey.
| | - Sara Sargazi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Saman Sargazi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran.
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Sonia Fathi-Karkan
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, 94531-55166, Iran
- Department of Advanced Sciences and Technologies in Medicine, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd 9414974877, Iran.
| | - Abbas Rahdar
- Department of Physics, University of Zabol, Zabol, P. O. Box. 98613-35856, Iran.
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Ravichandran SN, Kumar MM, Das A, Banerjee A, Veronica S, Sun-Zhang A, Zhang H, Anbalagan M, Sun XF, Pathak S. An Updated Review on Molecular Biomarkers in Diagnosis and Therapy of Colorectal Cancer. Curr Cancer Drug Targets 2024; 24:595-611. [PMID: 38031267 DOI: 10.2174/0115680096270555231113074003] [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: 07/26/2023] [Revised: 09/08/2023] [Accepted: 09/21/2023] [Indexed: 12/01/2023]
Abstract
Colorectal cancer is one of the most common cancer types worldwide. Since colorectal cancer takes time to develop, its incidence and mortality can be treated effectively if it is detected in its early stages. As a result, non-invasive or invasive biomarkers play an essential role in the early diagnosis of colorectal cancer. Many experimental studies have been carried out to assess genetic, epigenetic, or protein markers in feces, serum, and tissue. It may be possible to find biomarkers that will help with the diagnosis of colorectal cancer by identifying the genes, RNAs, and/or proteins indicative of cancer growth. Recent advancements in the molecular subtypes of colorectal cancer, DNA methylation, microRNAs, long noncoding RNAs, exosomes, and their involvement in colorectal cancer have led to the discovery of novel biomarkers. In small-scale investigations, most biomarkers appear promising. However, large-scale clinical trials are required to validate their effectiveness before routine clinical implementation. Hence, this review focuses on small-scale investigations and results of big data analysis that may provide an overview of the biomarkers for the diagnosis, therapy, and prognosis of colorectal cancer.
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Affiliation(s)
- Shruthi Nagainallur Ravichandran
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Makalakshmi Murali Kumar
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Alakesh Das
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Antara Banerjee
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Chennai, Tamil Nadu, 603103, India
| | - Suhanya Veronica
- Department of Medical Microbiology and NanoBiomedical Engineering, Medical University of Białystok, ul. Świerkowa, s20 B15-328, Białystok, Poland
| | - Alexander Sun-Zhang
- Department of Oncology- Pathology, BioClinicum, Karolinska Institutet, Stockholm, Sweden
| | - Hong Zhang
- School of Medicine, Department of Medical Sciences, Örebro University, Fakultetsgatan 1, 701 82 Örebro, Sweden
| | - Muralidharan Anbalagan
- School of Medicine, Tulane University School of Medicine, Tulane University, 1430 Tulane Ave, New Orleans, LA70112, United States
| | - Xiao-Feng Sun
- Department of Oncology and Department of Biomedical and Clinical Sciences, Linköping University, 58183, Linköping, Sweden
| | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Kelambakkam, Chennai, Tamil Nadu, 603103, India
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Shi S, Li J, Zhang Z, Tu H, Max C. Isorhapontigenin (ISO) inhibits malignant cell transformation, migration, and invasion through MEG3/NEDD9 signaling in Cr(VI)-transformed cells. Toxicol Appl Pharmacol 2023; 476:116661. [PMID: 37619952 PMCID: PMC10874125 DOI: 10.1016/j.taap.2023.116661] [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: 07/28/2023] [Revised: 08/15/2023] [Accepted: 08/18/2023] [Indexed: 08/26/2023]
Abstract
Cr(VI) compounds are confirmed human carcinogens. Maternally expression 3 (MEG3) is the first long non-coding RNA to be identified as a tumor suppressor. MEG3 is frequently downregulated or lost in various primary human tumor tissues and cancer cell lines. Downregulation of MEG3 is associated with cancer initiation, progression, and metastasis. Our previous study has revealed that MEG3 was lost and NEDD9 was upregulated in Cr(VI)-transformed cells compared to those in passage-matched normal BEAS-2B cells. Overexpression of MEG3 reduced NEDD9. β-Catenin was activated in Cr(VI)-transformed cells, overexpression of MEG3 or knockdown of NEDD9 inhibited the activation of β-Catenin. The results from the present study showed that isorhapontigenin (ISO) treatment is able to suppress cell proliferation, migration, and invasion of Cr(VI)-transformed cells. Further study showed that ISO treatment in Cr(VI)-transformed cells decreases the levels of Ki67, a biomarker for cell proliferation, and of cyclin D1, a regulator for the cell cycle. ISO elevated the MEG3 expression level in Cr(VI)-transformed cells. The DNA methylation transferases DNMT3a, DNMT3b, and DNMT1 levels were reduced upon ISO treatment. ISO treatment decreased both mRNA and protein levels of NEDD9. In addition, ISO treatment reduced the activation of β-catenin. Slug was upregulated and E-Cadherin was downregulated in Cr(VI)-transformed cells, treatment with ISO decreased Slug and increased E-Cadherin. This study demonstrated that ISO is a potent therapeutical agent against lung cancer induced by Cr(VI).
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Affiliation(s)
- Sophia Shi
- Department of Environmental Medicine, New York University Grossman School of Medicine, 341 East 25(th) Street, NY, New York 10010, United States of America
| | - Jingxia Li
- Department of Environmental Medicine, New York University Grossman School of Medicine, 341 East 25(th) Street, NY, New York 10010, United States of America
| | - Zhuo Zhang
- Department of Environmental Medicine, New York University Grossman School of Medicine, 341 East 25(th) Street, NY, New York 10010, United States of America
| | - Huailu Tu
- Department of Environmental Medicine, New York University Grossman School of Medicine, 341 East 25(th) Street, NY, New York 10010, United States of America
| | - Costa Max
- Department of Environmental Medicine, New York University Grossman School of Medicine, 341 East 25(th) Street, NY, New York 10010, United States of America.
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Aldayyeni H, Hjazi A, Shahab S, Gupta J, Alsaab HO, Motea YH, Alazbjee AAA, Romero-Parra RM, Obaid RF, Hussien BM, Hosseini-Fard SR. Functions, mechanisms, and clinical applications of lncRNA LINC00857 in cancer pathogenesis. Hum Cell 2023; 36:1656-1671. [PMID: 37378889 DOI: 10.1007/s13577-023-00936-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023]
Abstract
Emerging data indicated that long noncoding RNAs (lncRNAs) are crucial players in the biological processes via regulating epigenetics, transcription, and protein translation. A novel lncRNA, LINC00857, was indicated to upregulate in several types of cancer. In addition, LINC00857 was functionally related to the modulation of the cancer-linked behaviors, including invasion, migration, proliferation, epithelial-mesenchymal transition (EMT), cell cycle, and apoptosis. The importance of LINC00857 in cancer onset and development proposed that LINC00857 has major importance in the cancer progression and may be considered as a novel prognostic/diagnostic biomarker as well as a treatment target. Here, we retrospectively investigate the available progress in biomedical research investigating the functions of LINC00857 in cancer, focusing on finding the molecular mechanisms affecting various cancer-related behaviors and exploring its clinical applications.
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Affiliation(s)
| | - Ahmed Hjazi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | - Sana Shahab
- Department of Business Administration, College of Business Administration, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh, 11671, Saudi Arabia
| | - Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, 281406, India
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, 21944, Saudi Arabia
| | | | | | | | - Rasha Fadhel Obaid
- Department of Biomedical Engineering, Al-Mustaqbal University College, Babylon, Iraq
| | - Beneen M Hussien
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Seyed Reza Hosseini-Fard
- Department of Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Mishra A, Kumar R, Mishra SN, Vijayaraghavalu S, Tiwari NK, Shukla GC, Gurusamy N, Kumar M. Differential Expression of Non-Coding RNAs in Stem Cell Development and Therapeutics of Bone Disorders. Cells 2023; 12:cells12081159. [PMID: 37190068 PMCID: PMC10137108 DOI: 10.3390/cells12081159] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/26/2023] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
Stem cells' self-renewal and multi-lineage differentiation are regulated by a complex network consisting of signaling factors, chromatin regulators, transcription factors, and non-coding RNAs (ncRNAs). Diverse role of ncRNAs in stem cell development and maintenance of bone homeostasis have been discovered recently. The ncRNAs, such as long non-coding RNAs, micro RNAs, circular RNAs, small interfering RNA, Piwi-interacting RNAs, etc., are not translated into proteins but act as essential epigenetic regulators in stem cells' self-renewal and differentiation. Different signaling pathways are monitored efficiently by the differential expression of ncRNAs, which function as regulatory elements in determining the fate of stem cells. In addition, several species of ncRNAs could serve as potential molecular biomarkers in early diagnosis of bone diseases, including osteoporosis, osteoarthritis, and bone cancers, ultimately leading to the development of new therapeutic strategies. This review aims to explore the specific roles of ncRNAs and their effective molecular mechanisms in the growth and development of stem cells, and in the regulation of osteoblast and osteoclast activities. Furthermore, we focus on and explore the association of altered ncRNA expression with stem cells and bone turnover.
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Affiliation(s)
- Anurag Mishra
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, India
| | - Rishabh Kumar
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, India
| | - Satya Narayan Mishra
- Maa Gayatri College of Pharmacy, Dr. APJ Abdul Kalam Technical University, Prayagraj 211009, India
| | | | - Neeraj Kumar Tiwari
- Department of IT-Satellite Centre, Babasaheb Bhimrao Ambedkar University, Lucknow 226025, India
| | - Girish C Shukla
- Department of Biological, Geological, and Environmental Sciences, 2121 Euclid Ave., Cleveland, OH 44115, USA
- Center for Gene Regulation in Health and Disease, 2121 Euclid Ave., Cleveland, OH 44115, USA
| | - Narasimman Gurusamy
- Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
| | - Munish Kumar
- Department of Biochemistry, Faculty of Science, University of Allahabad, Prayagraj 211002, India
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Zhang Z, Shi S, Li J, Costa M. Long Non-Coding RNA MEG3 in Metal Carcinogenesis. TOXICS 2023; 11:toxics11020157. [PMID: 36851033 PMCID: PMC9962265 DOI: 10.3390/toxics11020157] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/23/2023] [Accepted: 01/31/2023] [Indexed: 06/06/2023]
Abstract
Most transcripts from human genomes are non-coding RNAs (ncRNAs) that are not translated into proteins. ncRNAs are divided into long (lncRNAs) and small non-coding RNAs (sncRNAs). LncRNAs regulate their target genes both transcriptionally and post-transcriptionally through interactions with proteins, RNAs, and DNAs. Maternally expressed gene 3 (MEG3), a lncRNA, functions as a tumor suppressor. MEG3 regulates cell proliferation, cell cycle, apoptosis, hypoxia, autophagy, and many other processes involved in tumor development. MEG3 is downregulated in various cancer cell lines and primary human cancers. Heavy metals, such as hexavalent chromium (Cr(VI)), arsenic, nickel, and cadmium, are confirmed human carcinogens. The exposure of cells to these metals causes a variety of cancers. Among them, lung cancer is the one that can be induced by exposure to all of these metals. In vitro studies have demonstrated that the chronic exposure of normal human bronchial epithelial cells (BEAS-2B) to these metals can cause malignant cell transformation. Metal-transformed cells have the capability to cause an increase in cell proliferation, resistance to apoptosis, elevated migration and invasion, and properties of cancer stem-like cells. Studies have revealed that MEG is downregulated in Cr(VI)-transformed cells, nickel-transformed cells, and cadmium (Cd)-transformed cells. The forced expression of MEG3 reduces the migration and invasion of Cr(VI)-transformed cells through the downregulation of the neuronal precursor of developmentally downregulated protein 9 (NEDD9). MEG3 suppresses the malignant cell transformation of nickel-transformed cells. The overexpression of MEG3 decreases Bcl-xL, causing reduced apoptosis resistance in Cd-transformed cells. This paper reviews the current knowledge of lncRNA MEG3 in metal carcinogenesis.
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Yan X, Jia H, Zhao J. LncRNA MEG3 attenuates the malignancy of retinoblastoma cells through inactivating PI3K /Akt/mTOR signaling pathway. Exp Eye Res 2023; 226:109340. [PMID: 36476400 DOI: 10.1016/j.exer.2022.109340] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 11/19/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
Retinoblastoma (RB) is the most common neoplasm found in the eye of children. There are increasing interests to develop targeted gene therapy for this disease. This study was performed to investigate the impact of long non-coding RNA (lncRNA) MEG3 on the biological features of RB cells. Vector overexpressing MEG3 was constructed and introduced into two RB cell lines. Transfected RB cells were assessed for proliferation, apoptosis, migration ability, expression levels of important genes in the PI3K/Akt/mTOR signaling pathway using qRT-PCR and Western blot analysis. Xenograft mouse models were constructed to determine the tumorigenicity of RB cells overexpressing MEG3. MEG3 mRNA level was significantly lower in RB cells than in non-cancer cells (p < 0.01). Overexpressing MEG3 resulted in significant reduction in cell proliferation (p < 0.05), migration (p < 0.01) and significant increase in apoptosis (p < 0.01). After overexpressing MEG3, p-PI3K, p-Akt and p-mTOR levels were significantly downregulated (p < 0.01). Furthermore, in the xenograft model, RB cells overexpressing MEG3 generated significantly smaller tumors as compared to RB cells that did not overexpress MEG3 (p < 0.05). Our data suggest that MEG3 increases apoptosis and reduces tumorigenicity of RB cells through inactivating the PI3K/Akt/mTOR pathway. Therefore, MEG3 could be further investigated as a potential new therapeutic agent and target for RB therapy.
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Affiliation(s)
- Xiaoxiao Yan
- Department of Ophthalmology, Handan Central Hospital, Handan, China
| | - Haibo Jia
- Department of Neurosurgery, Handan Central Hospital, Handan, China.
| | - Junbo Zhao
- Department of Ophthalmology, Handan Central Hospital, Handan, China
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Xu J, Wang X, Zhu C, Wang K. A review of current evidence about lncRNA MEG3: A tumor suppressor in multiple cancers. Front Cell Dev Biol 2022; 10:997633. [PMID: 36544907 PMCID: PMC9760833 DOI: 10.3389/fcell.2022.997633] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 11/22/2022] [Indexed: 12/12/2022] Open
Abstract
Long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3) is a lncRNA located at the DLK1-MEG3 site of human chromosome 14q32.3. The expression of MEG3 in various tumors is substantially lower than that in normal adjacent tissues, and deletion of MEG3 expression is involved in the occurrence of many tumors. The high expression of MEG3 could inhibit the occurrence and development of tumors through several mechanisms, which has become a research hotspot in recent years. As a member of tumor suppressor lncRNAs, MEG3 is expected to be a new target for tumor diagnosis and treatment. This review discusses the molecular mechanisms of MEG3 in different tumors and future challenges for the diagnosis and treatment of cancers through MEG3.
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Affiliation(s)
- Jie Xu
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xia Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Chunming Zhu
- Department of Family Medicine, Shengjing Hospital of China Medical University, Shenyang, China,*Correspondence: Chunming Zhu, ; Kefeng Wang,
| | - Kefeng Wang
- Department of Urology, Shengjing Hospital of China Medical University, Shenyang, China,*Correspondence: Chunming Zhu, ; Kefeng Wang,
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lncRNA MEG3 Inhibits the Proliferation and Growth of Glioma Cells by Downregulating Bcl-xL in the PI3K/Akt/NF-κB Signal Pathway. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3729069. [PMID: 35860793 PMCID: PMC9293524 DOI: 10.1155/2022/3729069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/24/2022] [Accepted: 06/28/2022] [Indexed: 11/23/2022]
Abstract
This study was conducted to investigate the impact and mechanisms of lncRNA MEG3 on glioma cells. lncRNA MEG3 was lowly expressed in glioma cells as compared to noncancer cells. Overexpression of MEG3 significantly downregulated the expression of Bcl-xL, slightly upregulated the expression of NF-κB p65 and IκBα, and reduced the proliferation of glioma cells with increased apoptosis and the migration and invasion ability. Subsequently, glioma cells overexpressing MEG3 had less tumorgenicity in xenograft mouse models. It is likely that MEG3 induces apoptosis in glioma cells via downregulating the Bcl-xL gene in the PI3K/Akt/NF-κB signal pathway to reduce the development of glioma.
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Long noncoding RNA Meg3 sponges miR-708 to inhibit intestinal tumorigenesis via SOCS3-repressed cancer stem cells growth. Cell Death Dis 2021; 13:25. [PMID: 34934045 PMCID: PMC8692598 DOI: 10.1038/s41419-021-04470-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 11/16/2021] [Accepted: 12/10/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) remains the most common gastrointestinal cancer and a leading cause of cancer deaths worldwide, with most showing pathologies indicating the malignant transformation of early stage intestinal stem cells. The long non-coding RNA Meg3, which functions as a tumor suppressor, has been reported to be abnormal in multiple tumorigenesis events; however, the underlying mechanism by which Meg3 contributes to the malignant proliferation of colonic stem cells remains unclear. METHODS We analyzed the expression levels of Meg3, miR-708, and SOCS3 in samples from Apc loss-of-function (Apcmin) mice and patients with CRC, particularly in colonic crypt cells. Apcmin mice and AMO/DSS-induced mice model (in vivo) and organoid culture system (in vitro) were used to explore the effect of the Meg3/miR-708/SOCS3 axis on tumorigenesis in the colon. In vitro, we performed RNApull-down, RNA immunoprecipitation, and luciferase reporter assays using DLD1 and RKO cell lines. FINDINGS The Meg3/miR-708/SOCS3 signaling axis plays a critical role in the early stage of CRC development. Our data showed Meg3 levels negatively correlate with miR-708 levels both in clinical samples and in the Apcmin mouse model, which indicated that Meg3 acts as a competitive endogenous RNA (ceRNA) of miR-708. Then, miR-708 served as an oncogene, inducing neoplasia in both Apcmin mice and cultured colonic organoids. Put together, miR-708 appears to promote malignant proliferation of colonic stem cells by targeting SOCS3/STAT3 signaling. INTERPRETATION These data revealed that Meg3 sponges miR-708 to inhibit CRC development via SOCS3-mediated repression of the malignant proliferation of colonic stem cells. The Meg3/miR-708/SOCS3 signaling axis provides potential targets for the diagnosis and treatment of CRC, particularly early stage CRC.
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Zhang Z, Wu Y, Yu C, Li Z, Xu L. Comprehensive analysis of immune related lncRNAs in the tumor microenvironment of stage II-III colorectal cancer. J Gastrointest Oncol 2021; 12:2232-2243. [PMID: 34790388 DOI: 10.21037/jgo-21-594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/19/2021] [Indexed: 11/06/2022] Open
Abstract
Background Long non-coding RNAs (lncRNAs) associated with immunological function have increasingly been found to act as effective prognostic biomarkers of the overall survival (OS) of colorectal cancer (CRC) patients. We sought to identify a signature of immune-related lncRNAs that offered value as a tool for the prospective prognostic evaluation of patients with stage II-III CRC. Methods The clinical and gene expression data of CRC patients in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases was obtained and separated into a training cohort composed of 202 samples, a test cohort of 124 samples from the GSE72970 dataset, and a validation cohort of 91 samples from the GSE143985 dataset. Results We firstly evaluated intratumoral immune cell infiltration by conducting a Single-sample gene set enrichment analyses (ssGSEA) analysis to separate patient tumors into those with low immune cell infiltration and those with high immune cell infiltration. We then compared lncRNA and mRNA expression profiles between these two tumor types, leading us to focus on eight lncRNAs identified within the resultant mRNA-lncRNA co-expression network. Multivariate Cox regression models were then utilized to detect an immune-associated lncRNA signature that offered value for prognostic model construction. Functional analyses revealed this lncRNA signature to be associated with key immunological pathways including the JAK-STAT signaling, T cell receptor signaling, and Rap1 signaling pathways. Conclusions Together, our results suggest that our immune-related 4 lncRNA signature can reliably predict stage II-III CRC patient prognosis, thereby guiding efforts to better understand this disease and to effectively treat it.
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Affiliation(s)
- Zan Zhang
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Yixin Wu
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Changyuan Yu
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Zhengtai Li
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Lida Xu
- College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
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Ng CT, Azwar S, Yip WK, Zahari Sham SY, Faisal Jabar M, Sahak NH, Mohtarrudin N, Seow HF. Isolation and Identification of Long Non-Coding RNAs in Exosomes Derived from the Serum of Colorectal Carcinoma Patients. BIOLOGY 2021; 10:biology10090918. [PMID: 34571795 PMCID: PMC8465981 DOI: 10.3390/biology10090918] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 08/20/2020] [Accepted: 08/22/2020] [Indexed: 12/12/2022]
Abstract
Simple Summary Treatment regimens for patients with advanced disease are limited and the mortality rate is high in these patients. A better understanding on pathogenesis and progression of cancer is critical for the development of new treatment strategies. In colorectal cancer (CRC), exosomes (secreted vesicles from cells) and long non-coding RNAs (lncRNAs) have been shown to play significant roles in disease development and progression. Long non-coding RNAs (lncRNAs) are present in the exosomes of serum and their profiles may potentially be useful as novel biomarkers for CRC patients and may provide a new insight in the pathogenesis and progression of CRC. Here, we compared the expression profiles of exosomal lncRNAs between non-cancer individuals and patients with colorectal carcinoma. The relative expression level of LINC00152 was found to be significantly lower in exosomes from sera of CRC patients as compared to non-cancer individuals whereas lncRNA H19 was significantly up-regulated in advanced-stages (stage III and IV) of CRC as compared to early-stages (stage I and II). Our data suggest that LINC00152 and H19 may play important roles in pathogenesis and progression of CRC. Abstract Long non-coding RNAs (lncRNAs) are non-coding RNAs consisting of more than 200 nucleotides in length. LncRNAs present in exosomes may play a critical role in the cellular processes involved in cancer pathogenesis and progression including proliferation, invasion, and migration of tumor cells. This paper aims to identify the differential expression of exosomal lncRNAs derived from the sera of non-cancer individuals and patients diagnosed with colorectal carcinoma. These differentially-expressed exosomal serum lncRNAs may provide an insight into the pathogenesis and progression of colorectal cancer (CRC). Serum exosomes and exosomes from SW480-7 cell culture supernatants were isolated and viewed by transmission electron microscope (TEM). The particle size distribution and protein markers of exosomes derived from SW480-7 were further analyzed using the Zetasizer Nano S instrument and western blotting technique. TEM showed that exosomes derived from serum and SW480-7 cells were round vesicles with sizes ranging from 50–200 nm. The exosomes derived from SW480-7 had an average diameter of 274.6 nm and contained the exosomal protein, ALIX/PDCD6IP. In our clinical studies, six lncRNAs, namely GAS5, H19, LINC00152, SNHG16, RMRP, and ZFAS1 were detected in the exosomes from sera of 18 CRC patients. Among these six lncRNAs, the expression level of LINC00152 was found to be significantly lower in CRC patients as compared to non-cancer individuals (p = 0.04) while lncRNA H19 was significantly up-regulated in advanced-stages (stage III and IV) of CRC (p = 0.04) as compared to early-stages (stage I and II). In conclusion, the detection of lower LINC00152 in exosomes of sera from CRC patients versus non-cancer individuals and H19 upregulation in advanced stages suggests that they may play important roles in pathogenesis and progression of CRC.
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Affiliation(s)
- Chin Tat Ng
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia; (C.T.N.); (S.A.); (W.K.Y.); (S.Y.Z.S.); (H.F.S.)
| | - Shamin Azwar
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia; (C.T.N.); (S.A.); (W.K.Y.); (S.Y.Z.S.); (H.F.S.)
| | - Wai Kien Yip
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia; (C.T.N.); (S.A.); (W.K.Y.); (S.Y.Z.S.); (H.F.S.)
| | - Siti Yazmin Zahari Sham
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia; (C.T.N.); (S.A.); (W.K.Y.); (S.Y.Z.S.); (H.F.S.)
| | - Mohd Faisal Jabar
- Department of Surgery, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia;
| | - Norren Haneezah Sahak
- Department of Pathology, Hospital Serdang, Jalan Puchong, Kajang 43000, Selangor, Malaysia;
| | - Norhafizah Mohtarrudin
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia; (C.T.N.); (S.A.); (W.K.Y.); (S.Y.Z.S.); (H.F.S.)
- Correspondence:
| | - Heng Fong Seow
- Department of Pathology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia; (C.T.N.); (S.A.); (W.K.Y.); (S.Y.Z.S.); (H.F.S.)
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Ma Y, Li Y, Tang Y, Tang N, Wang D, Li X. LINC00174 Facilitates Proliferation and Migration of Colorectal Cancer Cells via MiR-3127-5p/ E2F7 Axis. J Microbiol Biotechnol 2021; 31:1098-1108. [PMID: 34226413 PMCID: PMC9705992 DOI: 10.4014/jmb.2103.03001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/22/2021] [Accepted: 06/26/2021] [Indexed: 12/15/2022]
Abstract
The literature indicates that LINC00174 promotes the growth of colorectal cancer (CRC) cells, but its research needs to be enriched. We tried to explore the function and mechanism of LINC00174 in CRC cell proliferation and migration. Bioinformatics analysis predicted the binding relationship and expressions of lncRNA, miRNA and mRNA. Clinical study analyzes the relationship between LINC00174 and clinical data characteristics of CRC patients. The expressions of LINC00174, miR-3127-5p and E2F7 were verified by RT-qPCR, and the combination of the two was verified by dual luciferase analysis and RNA immunoprecipitation as needed. Western blot was used to detect the expression of EMT-related protein and E2F7 protein. Functional experiments were used to evaluate the function of the target gene on CRC cells. LINC00174 was up-regulated in CRC clinical samples and cells and was related to the clinical characteristics of CRC patients. High-expression of LINC00174, contrary to the effect of siLINC00174, promoted cell viability, proliferation, migration and invasion, up-regulated the expressions of N-Cadherin, Vimentin, E2F7, and inhibited the expression of E-Cadherin. MiR-3127-5p was one of the targeted miRNAs of LINC00174 and was down-regulated in CRC samples. In addition, miR-3127-5p mimic partially reversed the malignant phenotype of CRC cells induced by LINC00174. Besides, E2F7 was a target gene of miR-3127-5p, and LINC00174 repressed miR-3127-5p to regulate E2F7. Our research reveals that LINC00174 affected the biological characteristics of CRC cells through regulated miR-3127-5p/ E2F7 axis.
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Affiliation(s)
- Yuhong Ma
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Jinfeng District, Yinchuan City, Ningxia Hui Autonomous Region 750021, P.R. China,Corresponding author Phone: +86-0951-5920120 E-mail:
| | - Yuzhen Li
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Jinfeng District, Yinchuan City, Ningxia Hui Autonomous Region 750021, P.R. China
| | - Yuanyuan Tang
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Jinfeng District, Yinchuan City, Ningxia Hui Autonomous Region 750021, P.R. China
| | - Ning Tang
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Jinfeng District, Yinchuan City, Ningxia Hui Autonomous Region 750021, P.R. China
| | - Dengke Wang
- Department of Anatomy, Ningxia Medical University, Xingqing District, Yinchuan City, Ningxia Hui Autonomous Region 750003, P.R. China
| | - Xiaofei Li
- Department of Gastroenterology, People’s Hospital of Ningxia Hui Autonomous Region, Jinfeng District, Yinchuan City, Ningxia Hui Autonomous Region 750021, P.R. China
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Liu F, Song ZM, Wang XD, Du SY, Peng N, Zhou JR, Zhang MG. Long Non-coding RNA Signature for Liver Metastasis of Colorectal Cancers. Front Cell Dev Biol 2021; 9:707115. [PMID: 34307387 PMCID: PMC8297503 DOI: 10.3389/fcell.2021.707115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 06/14/2021] [Indexed: 12/30/2022] Open
Abstract
Colorectal cancer ranks within the top three cancers both in terms of incidence as well as deaths. Metastasis is often the major cause of mortality and liver is the primary and most common site to which colorectal cancers metastasize. We tested the prognostic ability of a long non-coding RNA (lncRNA) signature in liver metastatic colorectal cancers. We first evaluated expression levels of several lncRNAs in eight excised liver metastases from primary colorectal cancers and found significantly upregulated lncRNAs HOTAIR and MALAT1 along with significantly downregulated LOC285194. We further compared the expression levels of HOTAIR, MALAT1 and LOC285194 in primary colorectal tumors at the time of initial diagnosis and correlated them with disease progression and liver metastasis. HOTAIR and MALAT1 were significantly upregulated and LOC285194 was significantly downregulated in twelve patients who were diagnosed with liver metastasis within 5 years of initial diagnosis, compared to the five patients with no metastasis. A positive signature comprising of high HOTAIR/MALAT1 and low LOC285194 also correlated with progression to higher grade tumors. Thus, the lncRNA signature comprising of high HOTAIR/MALAT1 and low LOC285194 could be a prognostic signature for liver metastasis as well as overall poor survival.
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Affiliation(s)
- Fang Liu
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Zhen-Mei Song
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Xiao-Di Wang
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Shi-Yu Du
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Na Peng
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
| | - Jing-Rui Zhou
- Department of Gastroenterology, Shan GU Hospital, Handan, China
| | - Ming-Gang Zhang
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China
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Zhang K, Wang Q, Zhong B, Gong Z. LUCAT1 as an oncogene in tongue squamous cell carcinoma by targeting miR-375 expression. J Cell Mol Med 2021; 25:4543-4550. [PMID: 33787082 PMCID: PMC8107098 DOI: 10.1111/jcmm.15982] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 02/18/2020] [Accepted: 04/27/2020] [Indexed: 01/17/2023] Open
Abstract
Emerging studies suggested that lncRNAs play a crucial molecular role in cancer development and progression. LncRNA LUCAT1 has been proved as oncogenic molecular in lung cancer, glioma, osteosarcoma, renal carcinoma and oesophageal squamous cell carcinoma. However, its roles and function mechanisms in tongue squamous cell carcinoma (TSCC) are still unknown. We showed that the expression of LUCAT1 was up‐regulated in the TSCC cells and tissues and the higher LUCAT1 expression was associated with the poor overall survival (OS). Knockdown expression of LUCAT1 suppressed TSCC cell proliferation, cycle and migration. In addition, we demonstrated that miR‐375 overexpression inhibited the luciferase activity of LUCAT1 wild‐type and knockdown LUCAT1 promoted the miR‐375 expression in TSCC cell. Furthermore, we indicated that miR‐375 expression was down‐regulated in the TSCC cell lines and tissues and the lower expression of miR‐375 was associated with poor OS. The expression of miR‐375 was inversely correlated with LUCAT1 expression in the TSCC tissues. Knockdown LUCAT1 promoted TSCC cell proliferation, cell cycle and migration partly through regulating miR‐375 expression. In summary, this study suggested the tumorigenic effect of lncRNA LUCAT1 in TSCC cells by targeting miR‐375 expression.
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Affiliation(s)
- Kai Zhang
- Center of Stomatology, China-Japan Friendship Hospital, Beijing, China
| | - Qibao Wang
- Department of Endodontics, Jinan Stomatological Hospital, Shandong, China
| | - Bo Zhong
- Center of Stomatology, China-Japan Friendship Hospital, Beijing, China
| | - Zuode Gong
- Department of Endodontics, Jinan Stomatological Hospital, Shandong, China
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Liao Z, Nie H, Wang Y, Luo J, Zhou J, Ou C. The Emerging Landscape of Long Non-Coding RNAs in Colorectal Cancer Metastasis. Front Oncol 2021; 11:641343. [PMID: 33718238 PMCID: PMC7947863 DOI: 10.3389/fonc.2021.641343] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/29/2021] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers, with extremely high rates of morbidity and mortality. The main cause of death in CRC is distant metastasis; it affects patient prognosis and survival and is one of the key challenges in the treatment of CRC. Long non-coding RNAs (lncRNAs) are a group of non-coding RNA molecules with more than 200 nucleotides. Abnormal lncRNA expression is closely related to the occurrence and progression of several diseases, including cancer. Recent studies have shown that numerous lncRNAs play pivotal roles in the CRC metastasis, and reversing the expression of these lncRNAs through artificial means can reduce the malignant phenotype of metastatic CRC to some extent. This review summarizes the major mechanisms of lncRNAs in CRC metastasis and proposes lncRNAs as potential therapeutic targets for CRC and molecular markers for early diagnosis.
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Affiliation(s)
- Zhiming Liao
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Hui Nie
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Yutong Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
| | - Jingjing Luo
- Teaching and Research Room of Biochemistry and Molecular Biology, Medical School of Hunan University of Traditional Chinese Medicine, Changsha, China
| | - Jianhua Zhou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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The Role, Function, and Mechanism of Long Intergenic Noncoding RNA1184 (linc01184) in Colorectal Cancer. DISEASE MARKERS 2021; 2021:8897906. [PMID: 33564344 PMCID: PMC7867457 DOI: 10.1155/2021/8897906] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 01/21/2021] [Indexed: 01/07/2023]
Abstract
Background Long intergenic noncoding RNA1184 (linc01184) has been recently discovered; however, its role in human diseases is limited to date. The present study is aimed at investigating the expression pattern and mechanism of linc01184 in colorectal cancer (CRC) tumorigenesis. Methods The expression of linc01184 in CRC tissues and cell lines was compared with that in normal controls. The functions of linc01184 in CRC cells were identified by overexpression and small interfering RNA (siRNA) approaches in vitro. Meanwhile, the target gene prediction software, luciferase reporter, RNA pull-down, and western blotting assays were used to analyze the oncogenic mechanism. Results We found that linc01184 was obviously upregulated in CRC tissues and cells when compared to normal controls, and its upregulation had a positive association with the CRC progression. linc01184 knockdown significantly suppressed CRC cell proliferation and invasion and promoted apoptosis. Besides, linc01184 acted as a competitive endogenous RNA (ceRNA) by directly binding to microRNA-331 (miR-331), and its overexpression resulted in notable increases of human epidermal growth factor receptor 2 (HER2), phosphorylated Ser/Thr kinases (p-Akt), and extracellular regulated protein kinase 1/2 (p-ERK1/2) at posttranscriptional levels in CRC cells, which were antagonized by miR-331. Conclusions The findings reveal for the first time that linc01184 is an enhancer for the proliferation and invasion of CRC by functioning as a ceRNA through the linc01184-miR-331-HER2-p-Akt/ERK1/2 pathway regulatory network.
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Meng J, Ding T, Chen Y, Long T, Xu Q, Lian W, Liu W. LncRNA-Meg3 promotes Nlrp3-mediated microglial inflammation by targeting miR-7a-5p. Int Immunopharmacol 2021; 90:107141. [PMID: 33189612 DOI: 10.1016/j.intimp.2020.107141] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/15/2020] [Accepted: 10/25/2020] [Indexed: 12/13/2022]
Abstract
Recent studies have identified neuroinflammation as a significant contributor to the pathological process of traumatic brain injury (TBI) and as a potentially effective target for treatment. LncRNA maternally expressed gene 3 (Meg3) has further been observed to play a critical role in diverse biological processes, including microglial activation and the inflammatory response. However, its target gene and associated signaling pathway require further elucidation. This study found that lipopolysaccharide + ATP upregulated Meg3, promoted microglia activation, Nlrp3/caspase1 activation and inflammation, and markedly reduced miR-7a-5p. Overexpression of miR-7a-5p attenuated Meg3-induced microglial activation, but not Meg3 expression. Bioinformatic analysis and dual-luciferase assays indicated that Meg3 was a direct target of miR-7a-5p that negatively regulates miR-7a-5p expression. Further, we showed that Meg3 acted as a competing endogenous RNA for miR-7a-5p and induced microglial inflammation by regulating nod-like receptor protein 3 (Nlrp3) expression. Our study thus demonstrates Meg3 regulates microglia inflammation by targeting the miR-7a-5p /Nlrp3 pathway.
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Affiliation(s)
- Jiao Meng
- School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Ting Ding
- Department of Anesthesiology and Critical Care Medicine, Peking University First Hospital, Beijing 100034, China
| | - Yuhua Chen
- Department of Neurosurgery, Bijie First People's Hospital, Bijie 551700, China
| | - Tianlin Long
- Department of Neurosurgery, Bijie First People's Hospital, Bijie 551700, China
| | - Quanhua Xu
- Department of Neurosurgery, Bijie First People's Hospital, Bijie 551700, China
| | - Wenqing Lian
- Departmentof Critical Care Medicine, Peking University First Hospital, Beijing 100034, China
| | - Wei Liu
- Department of Neurosurgery, Bijie First People's Hospital, Bijie 551700, China.
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Xu C, Liu M, Jia D, Tao T, Hao D. lncRNA TINCR SNPs and Expression Levels Are Associated with Bladder Cancer Susceptibility. Genet Test Mol Biomarkers 2020; 25:31-41. [PMID: 33372851 DOI: 10.1089/gtmb.2020.0178] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Objective: The long-chain noncoding RNA (lncRNA) TINCR has been associated with the development and progression of bladder cancer. In this study, we analyzed the correlation between lncRNA TINCR single-nucleotide polymorphisms (SNPs) and bladder cancer susceptibility risk. Methods: The genotypes of the lncRNA TINCR rs2288947 and rs8113645 loci in 125 surgically treated bladder cancer patients and 125 controls were analyzed by Sanger sequencing. A dual-luciferase reporter gene assay was used to detect the binding of the microRNAs miR-1247-3p and miR-30c-2-3p with the lncRNA TINCR. The receiver operating characteristic curve was used to analyze the value of expression levels of the lncRNA TINCR and the microRNAs miR-1247-3p and miR-30c-2-3p in the diagnosis of bladder cancer. Results: The bladder cancer susceptibility risk of the rs2288947 G allele carriers was 2.32 times higher compared with the A allele carriers (95% confidence interval [CI]: 1.58-3.42, p < 0.01); The bladder cancer susceptibility risk of the rs8113645 T allele carriers was 0.33 times compared with the C allele carriers (95% CI: 0.19-0.55, p < 0.01). lncRNA TINCR was more highly expressed in bladder cancer tissues than controls (p < 0.01). The lncRNA TINCR rs2288947 A>G variation was associated with increased expression of lncRNA TINCR in bladder cancer tissues, and the rs8113645 C > T was associated with decreased expression. The expression levels of the lncRNA TINCR in cancer and paracancerous tissues showed a significant negative correlation with that of miR-1247-3p and miR-30c-2-3p (r = -0.89, -0.78, -0.81, and -0.66, all p < 0.01). The dual-luciferase reporter gene assay results indicate that the lncRNA TINCR rs2288947 G allele is the target of miR-1247-3p, and the rs8113645 C allele is the target of miR-30c-2-3p. Conclusion: The lncRNA TINCR rs2288947 A>G is associated with increased bladder cancer risk and rs8113645 C > T is associated with decreased susceptibility. These two SNP loci are associated with lncRNA TINCR expression levels; however, further studies are needed for validation.
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Affiliation(s)
- Chuanbing Xu
- Department of Urology, Zibo Central Hospital, Zibo, China
| | - Min Liu
- Department of Urology, Zibo Central Hospital, Zibo, China
| | - Dongsheng Jia
- Department of Urology, Zibo Central Hospital, Zibo, China
| | - Tingting Tao
- Department of Urology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China
| | - Dongfang Hao
- Department of Urology, Zibo Central Hospital, Zibo, China
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Omote N, Sauler M. Non-coding RNAs as Regulators of Cellular Senescence in Idiopathic Pulmonary Fibrosis and Chronic Obstructive Pulmonary Disease. Front Med (Lausanne) 2020; 7:603047. [PMID: 33425948 PMCID: PMC7785852 DOI: 10.3389/fmed.2020.603047] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 11/09/2020] [Indexed: 12/14/2022] Open
Abstract
Cellular senescence is a cell fate implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Cellular senescence occurs in response to cellular stressors such as oxidative stress, DNA damage, telomere shortening, and mitochondrial dysfunction. Whether these stresses induce cellular senescence or an alternative cell fate depends on the type and magnitude of cellular stress, but also on intrinsic factors regulating the cellular stress response. Non-coding RNAs, including both microRNAs and long non-coding RNAs, are key regulators of cellular stress responses and susceptibility to cellular senescence. In this review, we will discuss cellular mechanisms that contribute to senescence in IPF and COPD and highlight recent advances in our understanding of how these processes are influenced by non-coding RNAs. We will also discuss the potential therapeutic role for targeting non-coding RNAs to treat these chronic lung diseases.
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Affiliation(s)
- Norihito Omote
- Pulmonary, Critical Care and Sleep Medicine Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Maor Sauler
- Pulmonary, Critical Care and Sleep Medicine Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
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Jiang R, Hong X, Zhao Y, Wu W. Application of multiomics sequencing and advances in the molecular mechanisms of pancreatic neuroendocrine neoplasms. Cancer Lett 2020; 499:39-48. [PMID: 33246093 DOI: 10.1016/j.canlet.2020.11.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/10/2020] [Accepted: 11/10/2020] [Indexed: 12/14/2022]
Abstract
The incidence of pancreatic neuroendocrine neoplasms (PanNENs) has gradually increased. PanNENs comprise two subtypes with different clinical manifestations and molecular mechanisms: functional PanNENs and nonfunctional PanNENs. Excessive hormones and tumor progression severely affect the quality of life of patients or are even life threatening. However, the molecular mechanisms of hormone secretion and tumor progression in PanNENs have not yet been fully elucidated. At present, advancements in sequencing technologies have led to the exploration of new biological markers and an advanced understanding of molecular mechanisms in PanNENs. Multiomics sequencing could reveal differences and similarities in molecular features in different fields. However, sequencing studies of PanNENs are booming and should be summarized to integrate the current findings. In this review, we summarize the current status of multiomics sequencing in PanNENs to further guide its application. We explore mainly advancements in the genome, transcriptome, and DNA methylation fields. In addition, the cell origin of PanNENs, which has been a hot issue in sequencing research, is described in multiple fields.
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Affiliation(s)
- Rui Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Xiafei Hong
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China
| | - Yupei Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
| | - Wenming Wu
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Beijing, 100730, China.
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Tao Y, Yue P, Miao Y, Gao S, Wang B, Leng SX, Meng X, Zhang H. The lncRNA MEG3/miR-16-5p/VGLL4 regulatory axis is involved in etoposide-induced senescence of tumor cells. J Gene Med 2020; 23:e3291. [PMID: 33141998 DOI: 10.1002/jgm.3291] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 10/09/2020] [Accepted: 10/23/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND The senescence of tumor cells is an important tumor suppressor mechanism. The present study aimed to investigate the role of long non-coding RNA (lncRNA) MEG3 (maternally expressed gene 3) in the senescence process of tumor cells and its potential molecular mechanism by competitively binding with microRNA miR-16-5p to regulate the expression of VGLL4 (encoding vestigial like family member 4). METHODS We used etoposide to construct senescence models of tumor cells. The degree of cellular senescence was detected by senescence-associated β-galactosidase, cell cycle and senescence-associated secretory phenotype. The expression of lncRNA MEG3, miR-16-5p and VGLL4 in senescent or non-senescent cells was evaluated using a quantitative real-time reverse transcriptase-PCR (qRT-PCR) or western blotting. Dual luciferase reporter assays were used to detect the binding of miR-16-5p to lncRNA MEG3 and VGLL4. The mRNA and protein expression levels of senescence-related markers (p53, p21 and p16) were detected using qRT-PCR or western blotting. RESULTS Compared to the control group, the expression of lncRNA MEG3 and VGLL4 was significantly up-regulated in senescent cells. Knockdown of lncRNA MEG3 and VGLL4 reduced the degree of senescence and the expression of p21 and p16. lncRNA MEG3 interfered with the expression of miR-16-5p in senescent A549 and MCF-7 cells. The expression of VGLL4 was regulated by miR-16-5p in senescent A549 and MCF-7 cells. lncRNA MEG3 participated in the senescent progress of tumor cells induced by etoposide via the miR-16-5p/VGLL4 axis. CONCLUSIONS The present study has confirmed the regulatory role of the lncRNA MEG3/miR-16-5p/VGLL4 axis in the low-dose etoposide-induced tumor cell senescence model, which has potential clinical application with respect to treating malignant tumors.
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Affiliation(s)
- Ye Tao
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Peipei Yue
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, Liaoning Province, China
| | - Yongnan Miao
- Department of Urology, The Shengjing Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
| | - Shuting Gao
- Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, Liaoning Province, China
| | - Biao Wang
- Department of Biochemistry and Molecular Biology, School of Life Sciences, China Medical University, Shenyang, Liaoning Province, China
| | - Sean X Leng
- Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Xin Meng
- Department of Biochemistry and Molecular Biology, School of Life Sciences, China Medical University, Shenyang, Liaoning Province, China
| | - Haiyan Zhang
- Department of Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China
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Chen R, Lei S, Jiang T, She Y, Shi H. Regulation of Skeletal Muscle Atrophy in Cachexia by MicroRNAs and Long Non-coding RNAs. Front Cell Dev Biol 2020; 8:577010. [PMID: 33043011 PMCID: PMC7523183 DOI: 10.3389/fcell.2020.577010] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 08/26/2020] [Indexed: 12/14/2022] Open
Abstract
Skeletal muscle atrophy is a common complication of cachexia, characterized by progressive bodyweight loss and decreased muscle strength, and it significantly increases the risks of morbidity and mortality in the population with atrophy. Numerous complications associated with decreased muscle function can activate catabolism, reduce anabolism, and impair muscle regeneration, leading to muscle wasting. microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), types of non-coding RNAs, are important for regulation of skeletal muscle development. Few studies have specifically identified the roles of miRNAs and lncRNAs in cellular or animal models of muscular atrophy during cachexia, and the pathogenesis of skeletal muscle wasting in cachexia is not entirely understood. To develop potential approaches to improve skeletal muscle mass, strength, and function, a more comprehensive understanding of the known key pathophysiological processes leading to muscular atrophy is needed. In this review, we summarize the known miRNAs, lncRNAs, and corresponding signaling pathways involved in regulating skeletal muscle atrophy in cachexia and other diseases. A comprehensive understanding of the functions and mechanisms of miRNAs and lncRNAs during skeletal muscle wasting in cachexia and other diseases will, therefore, promote therapeutic treatments for muscle atrophy.
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Affiliation(s)
- Rui Chen
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Si Lei
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Ting Jiang
- Department of Radiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yanling She
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Huacai Shi
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute, Guangdong Second Provincial General Hospital, Guangzhou, China
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26
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Silencing of lncRNA EZR-AS1 inhibits proliferation, invasion, and migration of colorectal cancer cells through blocking transforming growth factor β signaling. Biosci Rep 2020; 39:220864. [PMID: 31693738 PMCID: PMC6851510 DOI: 10.1042/bsr20191199] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 09/24/2019] [Accepted: 10/07/2019] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNA (lncRNA) plays a key regulatory role in the pathogenesis of colorectal cancer (CRC). In the present study, the specific regulatory role of lncRNA ezrin antisense RNA 1 (EZR-AS1) on CRC was investigated. The expression of lncRNA EZR-AS1 was significantly up-regulated in CRC cell lines (HCT8, HCT116, HT29, and SW620 cells), which was significantly different from that of normal human fetal colonic mucosa cells (FHC cells) (P<0.01). HCT116 and HT29 cells were then transfected with EZR-AS1 shRNA (sh-EZR-AS1) to silence lncRNA EZR-AS1 (P<0.01). When compared with the Control, after transfection of SH-EZR-AS1, E-cadherin was up-regulated, Vimentin was down-regulated, the apoptosis rate was increased, the cell viability, wound healing rate, and the number of invasive cells were decreased in HCT116 and HT29 cells (P<0.05). Silencing of lncRNA EZR-AS also significantly reduced the tumor volume and weight in mice injected with sh-EZR-AS1-transfected HCT116 and HT29 cells (P<0.05). The regulatory relationship between lncRNA EZR-AS1 and transforming growth factor β (TGF-β) signaling was further identified in CRC cells. Silencing of lncRNA EZR-AS1 significantly down-regulated TGF-β, Smad2, and α-SMA expression in HCT116 and HT29 cells at the protein level (P<0.05). The intervention of SB431542 (a TGF-β receptor blocker) and silencing of Smad2 both significantly down-regulated lncRNA EZR-AS1 expression in HCT116 and HT29 cells (P<0.01). In conclusion, silencing of lncRNA EZR-AS1 inhibited the proliferation, invasion, migration, and epithelial–mesenchymal transition, and promoted the apoptosis of CRC cells through blocking TGF-β signaling.
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27
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Zhao B, Qu X, Lv X, Wang Q, Bian D, Yang F, Zhao X, Ji Z, Ni J, Fu Y, Xin G, Yu H. Construction and Characterization of a Synergistic lncRNA-miRNA Network Reveals a Crucial and Prognostic Role of lncRNAs in Colon Cancer. Front Genet 2020; 11:572983. [PMID: 33101392 PMCID: PMC7522580 DOI: 10.3389/fgene.2020.572983] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Accepted: 08/24/2020] [Indexed: 12/18/2022] Open
Abstract
Non-coding RNAs such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been found to be indispensable factors in carcinogenesis and cancer development. Numerous studies have explored the regulatory functions of these molecules and identified the synergistic interactions among lncRNAs or miRNAs, while those between lncRNAs and miRNAs remain to be investigated. In this study, we constructed and characterized an lncRNA–miRNA synergistic network following a four-step approach by integrating the regulatory pairs and expression profiles. The synergistic interactions with more shared regulatory mRNAs were found to have higher interactional intensity. Through the analysis of nodes in the network, we found that lncRNAs played roles that are more central and had similar synergistic interactions with their neighbors when compared with miRNAs. In addition, known colon adenocarcinoma (COAD)-related RNAs were found to be enriched in this synergistic network, with higher degrees, betweenness, and closeness. Finally, we proposed a risk score model to predict the clinical outcome for COAD patients based on two prognostic hub lncRNAs, MEG3 and ZEB1-AS1. Moreover, the hierarchical networks of these two lncRNAs could contribute to the understanding of the biological mechanism of tumorigenesis. For each lncRNA–miRNA interaction in the hub-related subnetwork and two hierarchical networks, we performed RNAup method to evaluate their binding energy. Our results identified two important lncRNAs with prognostic roles in colon cancer and dissected their regulatory mechanism involving synergistic interaction with miRNAs.
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Affiliation(s)
- Bin Zhao
- Department of Proctology, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Xiusheng Qu
- Department of Chemoradiotherapy, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Xin Lv
- Department of General Surgery, Samii Medical Center, Shenzhen, China
| | - Qingdong Wang
- Department of Anesthesiology, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Deqiang Bian
- Scientific Research Departments, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Fan Yang
- Department of Proctology, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Xingwang Zhao
- Department of Proctology, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Zhiwu Ji
- Department of Proctology, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Jian Ni
- Department of Proctology, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Yan Fu
- Department of Proctology, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Guorong Xin
- Department of Proctology, First Affiliated Hospital of Jiamusi University, Jiamusi, China
| | - Haitao Yu
- Department of Proctology, First Affiliated Hospital of Jiamusi University, Jiamusi, China
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Liao Q, Chen L, Zhang N, Xi Y, Hu S, Ng DM, Ahmed FYH, Zhao G, Fan X, Xie Y, Dai X, Jin Y, Ge J, Dong C, Zhang X, Guo J. Network analysis of KLF5 targets showing the potential oncogenic role of SNHG12 in colorectal cancer. Cancer Cell Int 2020; 20:439. [PMID: 32943987 PMCID: PMC7487661 DOI: 10.1186/s12935-020-01527-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 08/29/2020] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND KLF5 is a member of the Kruppel-like factor, subfamily of zinc finger proteins that are involved in cancers. KLF5 functions as a transcription factor and regulates the diverse protein-coding genes (PCGs) in colorectal cancer (CRC). However, the long non-coding RNAs (lncRNAs) regulated by KLF5 in CRC are currently unknown. METHODS In this study, we first designed a computational pipeline to determine the PCG and lncRNA targets of KLF5 in CRC. Then we analyzed the motif pattern of the binding regions for the lncRNA targets. The regulatory co-factors of KLF5 were then searched for through bioinformatics analysis. We also constructed a regulatory network for KLF5 and annotated its functions. Finally, one of the KLF5 lncRNA targets, SNHG12, was selected to further explore its expression pattern and functions in CRC. RESULTS We were able to identify 19 lncRNA targets of KLF5 and found that the motifs of the lncRNA binding sites were GC-enriched. Next, we pinpointed the transcription factors AR and HSF1 as the regulatory co-factors of KLF5 through bioinformatics analysis. Then, through the analysis of the regulatory network, we found that KLF5 may be involved in DNA replication, DNA repair, and the cell cycle. Furthermore, in the cell cycle module, the SNHG12 up-regulating expression pattern was verified in the CRC cell lines and tissues, associating it to CRC invasion and distal metastasis. This indicates that SNHG12 may play a critical part in CRC tumorigenesis and progression. Additionally, expression of SNHG12 was found to be down-regulated in CRC cell lines when KLF5 expression was knocked-down by siRNA; and a strong correlation was observed between the expression levels of SNHG12 and KLF5, further alluding to their regulatory relationship. CONCLUSIONS In conclusion, the network analysis of KLF5 targets indicates that SNHG12 may be a significant lncRNA in CRC.
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Affiliation(s)
- Qi Liao
- Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211 Zhejiang China
| | - Linbo Chen
- Department of Gastroenterology, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040 Zhejiang China
| | - Ning Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080 China
| | - Yang Xi
- Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211 Zhejiang China
| | - Shiyun Hu
- Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211 Zhejiang China
| | - Derry Minyao Ng
- Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211 Zhejiang China
| | - Fatma Yislam Hadi Ahmed
- Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211 Zhejiang China
| | - Guofang Zhao
- Hua Mei Hospital, University of Chinese Academy of Science, Ningbo, 315000 China
| | - Xiaoxiang Fan
- Hua Mei Hospital, University of Chinese Academy of Science, Ningbo, 315000 China
| | - Yangyang Xie
- Hua Mei Hospital, University of Chinese Academy of Science, Ningbo, 315000 China
| | - Xiaoyu Dai
- Hua Mei Hospital, University of Chinese Academy of Science, Ningbo, 315000 China
| | - Yanping Jin
- The Affiliated Hospital of School of Medicine, Ningbo University, Ningbo, 315020 China
| | - Jiaxin Ge
- The Affiliated Hospital of School of Medicine, Ningbo University, Ningbo, 315020 China
| | - Changzheng Dong
- Department of Preventative Medicine, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211 Zhejiang China
| | - Xinjun Zhang
- The Affiliated Hospital of School of Medicine, Ningbo University, Ningbo, 315020 China
| | - Junming Guo
- Department of Biochemistry and Molecular Biology, Zhejiang Provincial Key Laboratory of Pathophysiology, Ningbo University School of Medicine, Ningbo, 315211 Zhejiang China
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Budkova Z, Sigurdardottir AK, Briem E, Bergthorsson JT, Sigurdsson S, Magnusson MK, Traustadottir GA, Gudjonsson T, Hilmarsdottir B. Expression of ncRNAs on the DLK1-DIO3 Locus Is Associated With Basal and Mesenchymal Phenotype in Breast Epithelial Progenitor Cells. Front Cell Dev Biol 2020; 8:461. [PMID: 32612992 PMCID: PMC7308478 DOI: 10.3389/fcell.2020.00461] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 05/18/2020] [Indexed: 12/18/2022] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) and its reversed process mesenchymal-to-epithelial transition (MET) play a critical role in epithelial plasticity during development and cancer progression. Among important regulators of these cellular processes are non-coding RNAs (ncRNAs). The imprinted DLK1-DIO3 locus, containing numerous maternally expressed ncRNAs including the lncRNA maternally expressed gene 3 (MEG3) and a cluster of over 50 miRNAs, has been shown to be a modulator of stemness in embryonic stem cells and in cancer progression, potentially through the tumor suppressor role of MEG3. In this study we analyzed the expression pattern and functional role of ncRNAs from the DLK1-DIO3 locus in epithelial plasticity of the breast. We studied their expression in various cell types of breast tissue and revisit the role of the locus in EMT/MET using a breast epithelial progenitor cell line (D492) and its isogenic mesenchymal derivative (D492M). Marked upregulation of ncRNAs from the DLK1-DIO3 locus was seen after EMT induction in two cell line models of EMT. In addition, the expression of MEG3 and the maternally expressed ncRNAs was higher in stromal cells compared to epithelial cell types in primary breast tissue. We also show that expression of MEG3 is concomitant with the expression of the ncRNAs from the DLK1-DIO3 locus and its expression is therefore likely indicative of activation of all ncRNAs at the locus. MEG3 expression is correlated with stromal markers in normal tissue and breast cancer tissue and negatively correlated with the survival of breast cancer patients in two different cohorts. Overexpression of MEG3 using CRISPR activation in a breast epithelial cell line induced partial EMT and enriched for a basal-like phenotype. Conversely, knock down of MEG3 using CRISPR inhibition in a mesenchymal cell line reduced the mesenchymal and basal-like phenotype of the cell line. In summary our study shows that maternally expressed ncRNAs are markers of EMT and suggests that MEG3 is a novel regulator of EMT/MET in breast tissue. Nevertheless, further studies are needed to fully dissect the molecular pathways influenced by non-coding RNAs at the DLK1-DIO3 locus in breast tissue.
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Affiliation(s)
- Zuzana Budkova
- Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Anna Karen Sigurdardottir
- Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Eirikur Briem
- Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Jon Thor Bergthorsson
- Department of Laboratory Hematology, Landspitali - University Hospital, Reykjavik, Iceland
| | - Snævar Sigurdsson
- Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Magnus Karl Magnusson
- Department of Pharmacology and Toxicology, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Gunnhildur Asta Traustadottir
- Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Thorarinn Gudjonsson
- Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.,Department of Laboratory Hematology, Landspitali - University Hospital, Reykjavik, Iceland
| | - Bylgja Hilmarsdottir
- Stem Cell Research Unit, Biomedical Center, Department of Anatomy, Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland.,Department of Pathology, Landspitali - University Hospital, Reykjavik, Iceland
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30
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Qi FF, Yang Y, Zhang H, Chen H. Long non-coding RNAs: Key regulators in oxaliplatin resistance of colorectal cancer. Biomed Pharmacother 2020; 128:110329. [PMID: 32502843 DOI: 10.1016/j.biopha.2020.110329] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/22/2020] [Accepted: 05/23/2020] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies in the world with high relapse and mortality rates. Although oxaliplatin (OXA), a platinum-based anticancer drug, is widely used in CRC treatment, the resulting chemoresistance dramatically attenuates the drug efficacy and increases the failure rate of this therapy. Thus, the study on OXA-induced chemoresistance is extremely urgent. In recent years, emerging evidence has shown that lncRNAs play irreplaceable roles in drug resistance. However, we only have a limited knowledge of the lncRNAs that are closely related to oxaliplatin resistance in CRC. In present study, we identify and characterize these lncRNAs, including their functions, underlying mechanisms and possible applications.
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Affiliation(s)
- Fang-Fang Qi
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Yunyao Yang
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Haowen Zhang
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China; Queen Mary School, Medical Department, Nanchang University, Nanchang, Jiangxi 330006, PR China
| | - Hongping Chen
- Department of Histology and Embryology, Medical College of Nanchang University, Nanchang, Jiangxi 330006, PR China; Jiangxi Key Laboratory of Experimental Animals, Nanchang University, Nanchang, Jiangxi 330006, PR China.
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31
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Sun D, Wang Y, Wang H, Xin Y. The novel long non-coding RNA LATS2-AS1-001 inhibits gastric cancer progression by regulating the LATS2/YAP1 signaling pathway via binding to EZH2. Cancer Cell Int 2020; 20:204. [PMID: 32514249 PMCID: PMC7260745 DOI: 10.1186/s12935-020-01285-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 05/22/2020] [Indexed: 12/18/2022] Open
Abstract
Background To explore the expression pattern and role of the novel long non-coding RNA LATS2 antisense transcript 1 (LATS2-AS1-001) in gastric cancer (GC). Methods qRT-PCR was applied to evaluate LATS2-AS1-001 expression and correlation with LATS2 in GC. In vitro experiments were performed to investigate the role of LATS2-AS1-001 in GC cells. RNA immunoprecipitation (RIP) was performed to assess the interaction between EZH2 and LATS2-AS1-001. LATS2/YAP1 signaling pathway proteins were detected by immunoblot. Oncomine and KMPLOT data analysis was conducted to assess the prognostic value of YAP1 in GC. Results Decreased expression levels of LATS2-AS1-001 and LATS2 were confirmed in 357 GC tissues compared with the normal mucosa. A strong positive correlation between LATS2-AS1-001 and LATS mRNA expression was found in Pearson Correlation analysis (r = 0.719, P < 0.001). Furthermore, ROC curve analysis revealed areas under the curves for LATS2-AS1-001 and LATS2 of 0.7274 and 0.6865, respectively (P < 0.001), which indicated that LATS2-AS1-001 and LATS could be used as diagnostic indicators in GC. Moreover, ectopic expression of LATS2-AS1-001 decreased cell viability, induced G0/G1 phase arrest, and inhibited cell migration and invasion in GC cells. Mechanistically, overexpressing LATS2-AS1-001 upregulated LATS2 and induced YAP1 phosphorylation via binding to EZH2. Oncomine and KMPLOT database analysis demonstrated YAP1 was highly expressed in human GC samples, and high YAP1 expression predicted poor patient prognosis in GC. Conclusion This study revealed that lncRNA LATS2-AS1-001 might serve as a potential diagnostic index in GC and act as a suppressor of GC progression.
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Affiliation(s)
- Dan Sun
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute & General Surgery Institute, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 China
| | - Ying Wang
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute & General Surgery Institute, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 China.,Department of Oncology, Hanzhong Central Hospital, Hanzhong, 723000 China
| | - Huan Wang
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute & General Surgery Institute, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 China
| | - Yan Xin
- Laboratory of Gastrointestinal Onco-Pathology, Cancer Institute & General Surgery Institute, The First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001 China
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Esmaeili M, Keshani M, Vakilian M, Esmaeili M, Peymani M, Seyed Forootan F, Chau TL, Göktuna SI, Zaker SR, Nasr Esfahani MH, Ghaedi K. Role of non-coding RNAs as novel biomarkers for detection of colorectal cancer progression through interaction with the cell signaling pathways. Gene 2020; 753:144796. [PMID: 32450203 DOI: 10.1016/j.gene.2020.144796] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 05/06/2020] [Accepted: 05/19/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of the most common types of cancer which affects the colon and the rectum. Approximately one third of annual CRC mortality occurs due to the late detection of this type of cancer. Therefore, there is an urgent need for more powerful diagnostic and prognostic tools for identification and treatment of colorectal tumorigenesis. Non-coding RNAs (ncRNAs) have been implicated in the pathology of CRC and also linked to metastasis, proliferation, differentiation, migration, angiogenesis and apoptosis in numerous cancers. Recently, attention has turned towards ncRNAs as specific targets for diagnosis, prognosis and treatment of various types of cancers, including CRC. In this review, we have tried to outline the roles of ncRNAs, and their involvement in signaling pathways responsible for the progression of CRC.
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Affiliation(s)
- Mohadeseh Esmaeili
- Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran.
| | - Maryam Keshani
- Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran.
| | - Mehrdad Vakilian
- Department of Cell Regeneration and Advanced Therapies, Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Seville-CSIC, Sevilla, Spain; Department of Cellular Biology, Genetics and Physiology, Faculty of Science, University of Malaga (UMA), Málaga, Spain.
| | - Maryam Esmaeili
- Department of Cellular Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran; Department of Cellular Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Farzad Seyed Forootan
- Department of Cellular Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran; Legal Medicine Research Centre, Legal Medicine Organization, Tehran, Iran.
| | - Tieu Lan Chau
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.
| | - Serkan Ismail Göktuna
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey; National Nanotechnology Research Institute (UNAM), Bilkent University, Ankara, Turkey.
| | - Sayed Rasoul Zaker
- Department of Plant and Animal Biology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Mohammad Hossein Nasr Esfahani
- Department of Cellular Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran; Department of Cellular Biotechnology, Cell Science Research Centre, Royan Institute for Biotechnology, ACECR, Isfahan, Iran.
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Catana CS, Crișan CA, Opre D, Berindan-Neagoe I. Implications of Long Non-Coding RNAs in Age-Altered Proteostasis. Aging Dis 2020; 11:692-704. [PMID: 32489713 PMCID: PMC7220293 DOI: 10.14336/ad.2019.0814] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 08/14/2019] [Indexed: 12/15/2022] Open
Abstract
This review aims to summarize the current knowledge on how lncRNAs are influencing aging and cancer metabolism. Recent research has shown that senescent cells re-enter cell-cycle depending on intrinsic or extrinsic factors, thus restoring tissue homeostasis in response to age-related diseases (ARDs). Furthermore, maintaining proteostasis or cellular protein homeostasis requires a correct quality control (QC) of protein synthesis, folding, conformational stability, and degradation. Long non-coding RNAs (lncRNAs), transcripts longer than 200 nucleotides, regulate gene expression through RNA-binding protein (RBP) interaction. Their association is linked to aging, an event of proteostasis collapse. The current review examines approaches that lead to recognition of senescence-associated lncRNAs, current methodologies, potential challenges that arise from studying these molecules, and their crucial implications in clinical practice.
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Affiliation(s)
- Cristina-Sorina Catana
- Department of Medical Biochemistry, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Catalina-Angela Crișan
- Department of Neurosciences, “Iuliu Haţieganu” University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, Romania
| | - Dana Opre
- Department of Psychology, Babeș-Bolyai University, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- MEDFUTURE - Research Center for Advanced Medicine, Cluj-Napoca, Romania
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, Institute of Doctoral Studies, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
- Department of Experimental Pathology, “Prof. Dr. Ion Chiricuta” Oncology Institute, Cluj-Napoca, Romania
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Jafari D, Noorbakhsh F, Delavari A, Tavakkoli-Bazzaz J, Farashi-Bonab S, Abdollahzadeh R, Rezaei N. Expression level of long noncoding RNA NKILAmiR103-miR107 inflammatory axis and its clinical significance as potential biomarker in patients with colorectal cancer. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2020; 25:41. [PMID: 32582347 PMCID: PMC7306231 DOI: 10.4103/jrms.jrms_943_19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/07/2020] [Accepted: 02/23/2020] [Indexed: 12/13/2022]
Abstract
Background: Inflammatory cytokines have been observed in colorectal cancer (CRC) tissues and can promote the susceptibility to metastasis of CRC cells. Diverse regulatory mechanisms of long ncRNAs (lncRNAs) and microRNAs (miRNAs) involved in the inflammatory responses are associated with tumor progression. The aim of this research was to investigate the expression level of the nuclear factor-kappa B interacting lncRNA (NKILA)‐miR103-miR107 regulatory axis and its clinical significance as a potential biomarker in patients with CRC. Materials and Methods: In the present study, we investigated the expression levels of miR103, miR107, and NKILA in 21 paired CRC tissues and corresponding adjacent tissues, using real‐time polymerase chain reaction technique. Receiver operating characteristic (ROC) curve was used to analyze the prognostic value of biomarkers and to compare their predictive value. Results: It was found that the expression level of miR103 was significantly increased with the development of CRC (cancerous vs. corresponding normal tissues; 2.29 ± 1.65 vs. 1.16 ± 0.64, P = 0.003). Moreover, miR107 was upregulated in CRC tissues compared with paired normal tissues (2.1 ± 1.4 vs. 1.25 ± 0.83, P = 0.005), while NKILA displayed an opposite expression pattern versus miR103/107, but it was not statistically significant (3.69 ± 5.2 vs. 4.35 ± 5.99, P > 0.05). The ROC analysis demonstrated that miR103 had the best diagnostic ability performance with area under curve of 0.723 (0.545–0.901). Conclusion: We identified miR103/107 as tumor-promoting miRNAs with diagnostic value in cancer patients and presumptive negative regulators of NKILA, a potential cancer metastatic suppressor. Strategies that disrupt this regulatory axis might block CRC progression.
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Affiliation(s)
- Davood Jafari
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Delavari
- Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Tavakkoli-Bazzaz
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samad Farashi-Bonab
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Rasoul Abdollahzadeh
- Department of Medical Genetics, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity, Universal Scientific Education and Research Network, Tehran, Iran
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Liu H, Ye D, Chen A, Tan D, Zhang W, Jiang W, Wang M, Zhang X. A pilot study of new promising non-coding RNA diagnostic biomarkers for early-stage colorectal cancers. Clin Chem Lab Med 2020; 57:1073-1083. [PMID: 30978169 DOI: 10.1515/cclm-2019-0052] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 03/12/2019] [Indexed: 12/11/2022]
Abstract
Background Diagnostic biomarkers for the detection of colorectal cancers (CRCs) are lacking. Recent studies have demonstrated that circulating long non-coding RNAs have the potential to serve as biomarkers for the detection of cancers. We analyzed the significance of lncRNAs 91H, PVT-1 and MEG3 in the detection of CRC. Methods We examined the expression levels of 13 candidate lncRNAs in the plasma of 18 CRC patients and 20 non-cancerous controls. Then, we validated our findings by determining the expression levels of six promising lncRNAs in CRC tissues and normal colorectal tissues. Finally, we evaluated the clinical relevance of lncRNAs 91H, PVT-1 and MEG3 in the plasma of 58 CRC patients and 56 non-cancerous controls. Results Our data revealed that the expression levels of lncRNAs 91H, PVT-1 and MEG3 were significantly higher in plasma samples from CRC patients than in those from non-cancerous controls. The combination of 91H, PVT-1 and MEG3 could discriminate CRC patients from non-cancerous controls with an area under the receiver-operating curve (AUC) of 0.877 at a cut-off value of 0.3816, with a sensitivity of 82.76% and 78.57% specificity. More importantly, the combination of lncRNAs shows more sensitivity in the detection of early-stage CRC than the combination of CEA and CA19-9, biomarkers currently used for CRC detection (p < 0.0001). Conclusions lncRNAs 91H, PVT-1 and MEG3 are promising diagnostic biomarkers for early-stage CRC.
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Affiliation(s)
- Hanshao Liu
- Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, P.R. China.,General Surgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, P.R. China
| | - Deji Ye
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, P.R. China
| | - Aijun Chen
- General Surgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Dan Tan
- General Surgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Wenpeng Zhang
- General Surgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Wenxia Jiang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, P.R. China
| | - Mingliang Wang
- General Surgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Xiaoren Zhang
- Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, P.R. China.,General Surgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.,CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, P.R. China
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Jafarzadeh M, Soltani BM, Soleimani M, Hosseinkhani S. Epigenetically silenced LINC02381 functions as a tumor suppressor by regulating PI3K-Akt signaling pathway. Biochimie 2020; 171-172:63-71. [DOI: 10.1016/j.biochi.2020.02.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 02/18/2020] [Indexed: 12/21/2022]
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Fan X, Huang H, Ji Z, Mao Q. Long non-coding RNA MEG3 functions as a competing endogenous RNA of miR-93 to regulate bladder cancer progression via PI3K/AKT/mTOR pathway. Transl Cancer Res 2020; 9:1678-1688. [PMID: 35117516 PMCID: PMC8798796 DOI: 10.21037/tcr.2020.01.70] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 01/03/2020] [Indexed: 01/21/2023]
Abstract
BACKGROUND Maternally expressed gene 3 (MEG3) is a long non-coding RNA (lncRNA) and involved in progression of various human tumors. However, its underlying regulatory mechanism in tumorigenesis of bladder cancer (BC) remains unclear. To demonstrate effects of MEG3 on BC cell proliferation and elaborate its regulatory mechanism in BC. METHODS Aberrant expressions of MEG3 and miR-93-5p were induced by cell transfection. The mRNA and protein expression were analyzed using qRT-PCR and western blot. Cell proliferation was examined by CCK-8 assay and EdU staining. The targeted regulation effect of MEG3 on miR-93-5p was confirmed by luciferase reporter assay. The number of LC3 punctated cells was detected by immunofluorescence. Xeno-graft mouse model was constructed for in vivo validation. RESULTS MEG3 was down-regulated with increased expression of miR-93-5p in BC cells and tissues. Luciferase reporter assay showed that miR-93-5p was a direct target of MEG3 and was negatively regulated by MEG3. MEG3 overexpression inhibited cell proliferation and the expression of proliferation-, apoptosis- and autophagy-related proteins. The activation of PI3K/AKT/mTOR pathway was also suppressed with elevated cell apoptosis. miR-93-5p overexpression counteracted these results. In vivo experiments, we confirmed that miR-93-5p overexpression reversed the MEG3 overexpression-mediated suppression on tumor growth and protein expression. CONCLUSIONS lncRNA MEG3 could function as a competing endogenous RNA of miR-93 to regulate the tumorigenesis of BC via PI3K/AKT/mTOR pathway. The present research provided a new perspective to understanding the pathogenic mechanism of BC, and an effective therapeutic target for BC.
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Affiliation(s)
- Xinrong Fan
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Houfeng Huang
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Zhigang Ji
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Quanzong Mao
- Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China
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Chen R, Lei S, Jiang T, Zeng J, Zhou S, She Y. Roles of lncRNAs and circRNAs in regulating skeletal muscle development. Acta Physiol (Oxf) 2020; 228:e13356. [PMID: 31365949 DOI: 10.1111/apha.13356] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 07/26/2019] [Accepted: 07/27/2019] [Indexed: 02/06/2023]
Abstract
The multistep biological process of myogenesis is regulated by a variety of myoblast regulators, such as myogenic differentiation antigen, myogenin, myogenic regulatory factor, myocyte enhancer factor2A-D and myosin heavy chain. Proliferation and differentiation during skeletal muscle myogenesis contribute to the physiological function of muscles. Certain non-coding RNAs, including long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are involved in the regulation of muscle development, and the aberrant expressions of lncRNAs and circRNAs are associated with muscular diseases. In this review, we summarize the recent advances concerning the roles of lncRNAs and circRNAs in regulating the developmental aspects of myogenesis. These findings have remarkably broadened our understanding of the gene regulation mechanisms governing muscle proliferation and differentiation, which makes it more feasible to design novel preventive, diagnostic and therapeutic strategies for muscle disorders.
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Affiliation(s)
- Rui Chen
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute Guangdong Second Provincial General Hospital Guangzhou China
| | - Si Lei
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute Guangdong Second Provincial General Hospital Guangzhou China
| | - Ting Jiang
- Department of Radiology, The Third Affiliated Hospital Sun Yat‐sen University Guangzhou China
| | - Jie Zeng
- Department of Medical Ultrasonics, The Third Affiliated Hospital Sun Yat‐sen University Guangzhou China
| | - Shanyao Zhou
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute Guangdong Second Provincial General Hospital Guangzhou China
| | - Yanling She
- Guangdong Traditional Medical and Sports Injury Rehabilitation Research Institute Guangdong Second Provincial General Hospital Guangzhou China
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Ba MC, Ba Z, Long H, Cui SZ, Gong YF, Yan ZF, Lin KP, Wu YB, Tu YN. LncRNA AC093818.1 accelerates gastric cancer metastasis by epigenetically promoting PDK1 expression. Cell Death Dis 2020; 11:64. [PMID: 31988283 PMCID: PMC6985138 DOI: 10.1038/s41419-020-2245-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 01/07/2020] [Accepted: 01/09/2020] [Indexed: 12/18/2022]
Abstract
Gastric cancer (GC) is a highly prevalent type of metastatic tumor. The mechanisms underlying GC metastasis are poorly understood. Some long noncoding RNAs (lncRNAs) reportedly play key roles in regulating metastasis of GC. However, the biological roles of five natural antisense lncRNAs (AC093818.1, CTD-2541M15.1, BC047644, RP11-597M12.1, and RP11-40A13.1) in GC metastasis remain unclear. In this study, the expression of these lncRNAs was measured by quantitative reverse transcription-polymerase chain reaction. Migration and invasion were evaluated by wound-healing and the Transwell assay, respectively. Stable cells were injected into the tail veins of nude mice. Sections of collected lung and liver tissues were stained using hematoxylin and eosin. Protein expression was analyzed by western blot. RNA immunoprecipitation (RIP) assay was used to verify whether the STAT3 and SP1 transcription factors bound to AC093818.1 in GC cells. Expression levels of the five lncRNAs, especially AC093818.1, were significantly upregulated in metastatic GC tissues relative to those in nonmetastatic GC tissues. AC093818.1 expression was correlated with invasion, lymphatic metastasis, distal metastasis, and tumor-node-metastasis stage. AC093818.1 expression was highly sensitive and specific in the diagnosis of metastatic or nonmetastatic GC. AC093818.1 overexpression promoted GC migration and invasion in vitro and in vivo. AC093818.1 overexpression increased PDK1, p-AKT1, and p-mTOR expression levels. AC093818.1 silencing decreased these expressions. AC093818.1 bound to transcription factors STAT3 and SP1, and SP1 or STAT3 silencing could alleviated the effect of AC093818.1 overexpression. The data demonstrate that lncRNA AC093818.1 accelerates gastric cancer metastasis by epigenetically promoting PDK1 expression. LncRNA AC093818.1 may be a potential therapeutic target for metastatic GC.
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Affiliation(s)
- Ming-Chen Ba
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, P.R. China.
| | - Zheng Ba
- Intensive Care Unit, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
| | - Hui Long
- Department of Pharmacy, Guangzhou Dermatology Institute, Guangzhou, 510095, P.R. China
| | - Shu-Zhong Cui
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, P.R. China
| | - Yuan-Feng Gong
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, P.R. China
| | - Zhao-Fei Yan
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, P.R. China
| | - Kun-Peng Lin
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, P.R. China
| | - Yin-Bing Wu
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, P.R. China
| | - Yi-Nuo Tu
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, P.R. China
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Ali MA, Shaker OG, Alazrak M, AbdelHafez MN, Khalefa AA, Hemeda NF, Abdelmoktader A, Ahmed FA. Association analyses of a genetic variant in long non-coding RNA MEG3 with breast cancer susceptibility and serum MEG3 expression level in the Egyptian population. Cancer Biomark 2020; 28:49-63. [PMID: 32176630 DOI: 10.3233/cbm-191072] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND LncRNA MEG3 rs7158663 has been shown to confer cancer susceptibility, maybe through altering its gene expression level. OBJECTIVE We aimed to weigh the effect of rs7158663 on MEG3 serum level and breast cancer susceptibility. METHODS We genotyped rs7158663 G > A and measured serum MEG3 in 150 breast cancer, 95 fibroadenoma , and 154 controls by the TaqMan method. RESULTS The presence of rs7158663 G > A is a risk factor for breast cancer among fibroadenoma patients and controls, AA vs. GG genotypes (OR = 6.320, 95% CI = 2.587-15.439, P< 0.0001 when compared to controls and OR = 10.825, 95% CI = 1.929-60.742, P= 0.007 when compared to fibroadenoma). Decreased serum MEG3 was observed in breast cancer group when compared with fibroadenoma and/or controls [median (IQR) = 0.43 (0.27-0.55)] (P< 0.0001). However, increased serum MEG3 was noted in fibroadenoma group when compared with controls (P< 0.0001). A significance decreased serum MEG3 was found to be associated with mutant A allele than with wild G allele (P< 0.0001). The results showed that rs7158663 and lower MEG3 were significantly associated with patients with higher TNM staging and larger tumor size > 5 cm. CONCLUSION The presence of both rs7158663 and low MEG3 are diagnostic and unfavorable prognostic factors for BC patients.
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Affiliation(s)
- Marwa A Ali
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Olfat G Shaker
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Marwa N AbdelHafez
- Department of Medical Oncology, National Cancer Institute, Cairo University, Egypt
| | - Abeer A Khalefa
- Department of Physiology, Faculty of Medicine, Zagazig University, Egypt
| | - Nada F Hemeda
- Department of Genetics, Faculty of Agriculture, Fayoum University, Fayoum, Egypt
| | - Abdelrahman Abdelmoktader
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
| | - Fatma A Ahmed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Fayoum University, Fayoum, Egypt
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Wang X, Peng L, Gong X, Zhang X, Sun R. LncRNA HIF1A-AS2 promotes osteosarcoma progression by acting as a sponge of miR-129-5p. Aging (Albany NY) 2019; 11:11803-11813. [PMID: 31866584 PMCID: PMC6949059 DOI: 10.18632/aging.102448] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 11/04/2019] [Indexed: 01/17/2023]
Abstract
Increasing studies have demonstrated that long noncoding RNAs (lncRNAs) play vital roles in tumor development and progression. However, the relationship between osteosarcoma and HIF1AAS2 remains unknown. The expression of HIF1AAS2 and miR-129-5p was detected in osteosarcoma cell lines and samples via qRT-PCR. Cell Counting Kit-8 (CCK-8) and invasion assays were performed to determine cell proliferation and invasion ability, and a dual luciferase reporter assay was performed to determine the interaction between HIF1AAS2 and miR-129-5p. We showed that the expression of HIF1A-AS2 was upregulated in the osteosarcoma samples compared with the expression in noncancerous samples. Moreover, patients with high HIF1A-AS2 expression had a shorter overall survival. Ectopic expression of HIF1A-AS2 enhanced osteosarcoma cell proliferation, cell cycle progression and invasion. We found that overexpression of miR-129-5p decreased the luciferase activity of wild-type (WT) HIF1A-AS2 but not mutant HIF1A-AS2. Ectopic expression of HIF1A-AS2 suppressed miR-129-5p expression in MG-63 cells. We demonstrated that miR-129-5p was downregulated in osteosarcoma and was negatively associated with HIF1A-AS2 expression. Furthermore, ectopic expression of miR-129-5p suppressed osteosarcoma cell proliferation, cell cycle progression and invasion. In addition, overexpression of HIF1A-AS2 promoted cell proliferation, cell cycle progression and invasion of osteosarcoma cells through the modulation of miR-129-5p. These results indicated that HIF1A-AS2 might be a potential therapeutic target for osteosarcoma.
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Affiliation(s)
- Xuesong Wang
- No.1 Spinal Department of No.2 Affiliated Hospital of Qingdao University, Qingdao Central Hospital, Shandong, China
| | - Lei Peng
- Library of No.2 Affiliated Hospital of Qingdao University, Qingdao Central Hospital, Shandong, China
| | - Xiaojin Gong
- No.1 Spinal Department of No.2 Affiliated Hospital of Qingdao University, Qingdao Central Hospital, Shandong, China
| | - Xiugong Zhang
- No.1 Spinal Department of No.2 Affiliated Hospital of Qingdao University, Qingdao Central Hospital, Shandong, China
| | - Ruifu Sun
- No.1 Spinal Department of No.2 Affiliated Hospital of Qingdao University, Qingdao Central Hospital, Shandong, China
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Huang Y, Sun H, Ma X, Zeng Y, Pan Y, Yu D, Liu Z, Xiang Y. HLA-F-AS1/miR-330-3p/PFN1 axis promotes colorectal cancer progression. Life Sci 2019; 254:117180. [PMID: 31863778 DOI: 10.1016/j.lfs.2019.117180] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 12/10/2019] [Accepted: 12/14/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Accumulating Studies implies that long-chain non-coding RNA (lncRNA) plays a vital regulatory role in the occurrence and progression of tumors. This study aimed to explore the function and mechanism of lncRNA HLA-F antisense RNA 1 (HLA-F-AS1) in colorectal cancer (CRC). METHODS Expressions of HLA-F-AS1, miR-330-3p and profilin 1 (PFN1) mRNA in CRC tissues were detected by RT-PCR. MTT assay was used to detect cell proliferation, and Transwell assay was used to detect cell migration and invasion. In addition, PFN1 and apoptosis-related protein Bcl-2 associated X (Bax) and B cell lymphoma/leukmia-2 (Bcl2) were detected by western blot. Interactions between miR-330-3p and HLA-F-AS1 or the 3'UTR of PFN1 were predicted and determined by bioinformatics analysis and luciferase reporter assay. RESULTS Expressions of HLA-F-AS1 and PFN1 were significantly up-regulated while miR-330-3p was significantly down-regulated in CRC tissues and cell lines. Over-expressions of HLA-F-AS1 or transfection of miR-330-3p inhibitors could promote the proliferation, migration and invasion and block apoptosis of CRC cells, whereas knockdown of HLA-F-AS1 or transfection of miR-330-3p mimics led to the opposite effects. Additionally, HLA-F-AS1 could down-regulate miR-330-3p via sponging it. HLA-F-AS1 also enhanced the expressions of PFN1, which was validated as a target gene of miR-330-3p. CONCLUSION HLA-F-AS1 promoted CRC progression via regulating miR-330-3p/PFN1 axis.
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Affiliation(s)
- Yongguo Huang
- Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, Hubei Province, China
| | - Hong Sun
- Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, Hubei Province, China
| | - Xiang Ma
- Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, Hubei Province, China
| | - Ye Zeng
- Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, Hubei Province, China
| | - Yang Pan
- Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, Hubei Province, China
| | - Dongyang Yu
- Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, Hubei Province, China
| | - Zhisheng Liu
- Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, Hubei Province, China
| | - Yun Xiang
- Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430016, Hubei Province, China.
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Improving the therapeutic efficiency of noncoding RNAs in cancers using targeted drug delivery systems. Drug Discov Today 2019; 25:718-730. [PMID: 31758914 DOI: 10.1016/j.drudis.2019.11.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 11/01/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022]
Abstract
The delivery of noncoding (nc)RNA to target cancer stem cells and metastatic tumors has shown many positive outcomes, resulting in improved and more efficient treatment strategies. The success of therapeutic RNA depends solely on passing cellular barriers to reach the target site, where it binds to the mRNA of the interest. By 2018, 20 clinical trials had been initiated, most focusing on cancer and diabetes, with some progressing to Phase II clinical trials testing the safety and efficacy of small interfering (si)RNA. Many challenges limit RNA interference (RNAi) and miRNA usage in vivo; therefore, various approaches have been developed to promote ncRNA efficiency and stability. In this review, we focus on targeting the tumor microenvironment (TME) via the modification of delivery systems utilizing nanotechnology-based delivery approaches.
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Yin S, Dou J, Yang G, Chen F. Long non-coding RNA XIST expression as a prognostic factor in human cancers: A meta-analysis. Int J Biol Markers 2019; 34:327-333. [PMID: 31566056 DOI: 10.1177/1724600819873010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A large number of literature has shown that high expression of X inactive-specific transcript (XIST) is associated with poor prognosis and metastasis of cancer in patients. However, most of this literature is limited by the small sample sizes and discrete outcomes. Therefore, a meta-analysis was performed to investigate the relation between XIST expression and tumor node metastasis (TNM) stage, lymph node metastasis, distant metastasis, and overall survival of cancer patients. We searched for literature in PubMed, Embase, and Web of Science. The pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to evaluate the association of XIST expression with prognosis and clinicopathological characteristics of cancer patients. Finally, a total of 14 articles involving 1123 patients were included in this meta-analysis. The results suggested that high expression of XIST has a significant relationship with a relatively poor overall survival for patients with malignant tumors (HR 1.82; 95% CI 1.32, 2.52; P = 0.0003). Moreover, high expression of XIST was significantly associated with poor TNM stage (OR 3.64; 95% CI 2.62, 5.07; P < 0.0001), lymph node metastasis (OR 2.39; 95% CI 1.65, 3.46; P < 0.0001) and distant metastasis (OR 2.84; 95% CI 1.90, 4.23; P < 0.0001). In conclusion, high expression of lncRNA XIST may be a predictive factor of poor prognosis in human cancers.
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Affiliation(s)
- Shuai Yin
- Department of Gastroenterology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, Hubei, China.,Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jiayu Dou
- Department of Microbiology & Immunology, Mcgill University, Montreal, Quebec, Canada
| | - Guifang Yang
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Fangfang Chen
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Galamb O, Barták BK, Kalmár A, Nagy ZB, Szigeti KA, Tulassay Z, Igaz P, Molnár B. Diagnostic and prognostic potential of tissue and circulating long non-coding RNAs in colorectal tumors. World J Gastroenterol 2019; 25:5026-5048. [PMID: 31558855 PMCID: PMC6747286 DOI: 10.3748/wjg.v25.i34.5026] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 07/26/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are members of the non-protein coding RNA family longer than 200 nucleotides. They participate in the regulation of gene and protein expression influencing apoptosis, cell proliferation and immune responses, thereby playing a critical role in the development and progression of various cancers, including colorectal cancer (CRC). As CRC is one of the most frequently diagnosed malignancies worldwide with high mortality, its screening and early detection are crucial, so the identification of disease-specific biomarkers is necessary. LncRNAs are promising candidates as they are involved in carcinogenesis, and certain lncRNAs (e.g., CCAT1, CRNDE, CRCAL1-4) show altered expression in adenomas, making them potential early diagnostic markers. In addition to being useful as tissue-specific markers, analysis of circulating lncRNAs (e.g., CCAT1, CCAT2, BLACAT1, CRNDE, NEAT1, UCA1) in peripheral blood offers the possibility to establish minimally invasive, liquid biopsy-based diagnostic tests. This review article aims to describe the origin, structure, and functions of lncRNAs and to discuss their contribution to CRC development. Moreover, our purpose is to summarise lncRNAs showing altered expression levels during tumor formation in both colon tissue and plasma/serum samples and to demonstrate their clinical implications as diagnostic or prognostic biomarkers for CRC.
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Affiliation(s)
- Orsolya Galamb
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest H-1088, Hungary
| | - Barbara K Barták
- 2nd Department of Internal Medicine, Semmelweis University, Budapest H-1088, Hungary
| | - Alexandra Kalmár
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest H-1088, Hungary
| | - Zsófia B Nagy
- 2nd Department of Internal Medicine, Semmelweis University, Budapest H-1088, Hungary
| | - Krisztina A Szigeti
- 2nd Department of Internal Medicine, Semmelweis University, Budapest H-1088, Hungary
| | - Zsolt Tulassay
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest H-1088, Hungary
| | - Peter Igaz
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest H-1088, Hungary
- 2nd Department of Internal Medicine, Semmelweis University, Budapest H-1088, Hungary
| | - Béla Molnár
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest H-1088, Hungary
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Wang H, Huang C, Yao X. The functions of long non-coding RNAs in colorectal cancer. Transl Cancer Res 2019; 8:2192-2204. [PMID: 35116969 PMCID: PMC8797667 DOI: 10.21037/tcr.2019.08.23] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 07/25/2019] [Indexed: 02/05/2023]
Abstract
Colorectal cancer (CRC) is the third most prevalent malignant neoplasm worldwide. Recently, in terms of the mechanism of CRC, most studies have focused on protein-coding genes. However, studies have increasingly shown that long non-coding RNAs (lncRNAs) play crucial roles in the proliferation and metastasis of CRC. Investigating this molecular mechanism may provide potential diagnostic tools and therapeutic targets for CRC. This review closely examines the dysregulation of lncRNAs in CRC. On account of different mechanisms being involved in the occurrence and development of CRC, there are several categories of lncRNAs, including lncRNAs related to the Wnt/β-catenin pathway, epithelial mesenchymal transition, epigenetic regulation, angiopoiesis, and chemoresistance. This review summarizes lncRNAs related to the progression of CRC, which may provide insight into the mechanisms and potential markers for prognostic prediction and monitoring relapse of CRC.
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Affiliation(s)
- Huaiming Wang
- Second Clinical Medical College, Southern Medical University, Guangzhou 510515, China
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
- Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
| | - Chengzhi Huang
- Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
- Medical College, Shantou University, Shantou 515063, China
| | - Xueqing Yao
- Second Clinical Medical College, Southern Medical University, Guangzhou 510515, China
- Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China
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The role of long noncoding RNA in major human disease. Bioorg Chem 2019; 92:103214. [PMID: 31499258 DOI: 10.1016/j.bioorg.2019.103214] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 08/20/2019] [Accepted: 08/20/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) are RNAs whose transcripts are longer than 200nt in length and lack the ability to encode proteins due to lack of specific open reading frames. lncRNAs were once thought to represent transcriptome noise or garbage sequences and a byproduct of RNA polymerase II (Pol II), and thereby ignored by researchers. In fact, lncRNA was involved in a wide variety of physiological and pathological processes in organisms. Comprehensive study of lncRNA does not only provide explanations to the physiological and pathological processes of living organisms, but also gives us new perspectives to the diagnosis, prevention and treatment of some clinical diseases. Therefore, the study of lncRNA is a very broad field of great research value and significance. RESULTS This article reviews the function of lncRNAs and their role in major human diseases. CONCLUSIONS Numerous studies show that lncRNA might serve as a biomarker for diagnosis and prognosis of various diseases. Compared to conventional biomarkers, lncRNA seems to have a higher diagnostic and prognostic values, not only because of their tissue and disease specific expression patterns, but also due to their highly stable physical and chemical properties.
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Guo Z, Zhou C, Zhong X, Shi J, Wu Z, Tang K, Wang Z, Song Y. The long noncoding RNA CTA-941F9.9 is frequently downregulated and may serve as a biomarker for carcinogenesis in colorectal cancer. J Clin Lab Anal 2019; 33:e22986. [PMID: 31343781 PMCID: PMC6868415 DOI: 10.1002/jcla.22986] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 07/02/2019] [Accepted: 07/03/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) participate in the carcinogenesis of many different cancers. This study aimed to detect expression of lncRNA CTA-941F9.9 in colorectal cancer tissues compared with matched nontumorous adjacent tissues (NATs). Moreover, we investigated whether this molecule is able to influence carcinogenesis in colorectal cancer (CRC). METHODS Colorectal cancer tissues and NATs from two cohorts of patients were examined. Quantitative PCR was performed to quantify levels of CTA-941F9.9 expression in these samples. The association between CTA-941F9.9 expression and clinicopathological features, including receiver operating characteristic (ROC) curves, was also analyzed to evaluate the diagnostic value of CTA-941F9.9 in CRC. Potential effects of lncRNA CTA-941F9.9 on CRC cells were assessed via autophagy, transwell assay, CCK8 assays, and flow cytometry. RESULTS Our experimental results showed lncRNA CTA-941F9.9 to be significantly downregulated in CRC tissues in both cohorts, with areas under the ROC curve (AUC) of 0.802 and 0.876. However, no significant correlations between CTA-941F9.9 expression levels and clinicopathological characteristics or patient outcomes were observed. We also found that CTA-941F9.9 promotes autophagy in CRC cell lines but no significant function of CTA-941F9.9 in regulating cancer cell proliferation or migration. CONCLUSIONS LncRNA CTA-941F9.9 is frequently downregulated in CRC compared with NATs and might play an important role in CRC carcinogenesis.
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Affiliation(s)
- Zhexu Guo
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Cen Zhou
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Xi Zhong
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Jinxin Shi
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Zhonghua Wu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Kaiwen Tang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
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Maternally expressed gene 3 (MEG3): A tumor suppressor long non coding RNA. Biomed Pharmacother 2019; 118:109129. [PMID: 31326791 DOI: 10.1016/j.biopha.2019.109129] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 06/10/2019] [Accepted: 06/12/2019] [Indexed: 12/12/2022] Open
Abstract
Maternally expressed gene 3 (MEG3) is a long non-coding RNA (lncRNA) located on chromosome 14q32.3. Direct sequencing experiments have shown monoallelic expression of this lncRNA. Several studies have shown down-regulation of this lncRNA in human cancers. In some cases, hypermethylation of the promoter region has been suggested as the underlying mechanism. Functional studies have shown that this lncRNA controls expression of several tumor suppressor genes and oncogenes among them are p53, RB, MYC and TGF-β. Through regulation of Wnt-β-catenin pathway, it also affects epithelial-mesenchymal transition. In vitro studies have demonstrated contribution of MEG3 in defining response to chemotherapeutic agents such as paclitaxel, cisplatin and oxaliplatin. Certain polymorphisms within MEG3 are implicated in cancer risk (rs7158663, rs4081134 and rs11160608) or therapeutic response of cancer patients (rs10132552). Taken together, this lncRNA is regarded as a putative cancer biomarker and treatment target. In the current review, several aspects of the participation of MEG3 in carcinogenesis are discussed.
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Yi J, Chen B, Yao X, Lei Y, Ou F, Huang F. Upregulation of the lncRNA MEG3 improves cognitive impairment, alleviates neuronal damage, and inhibits activation of astrocytes in hippocampus tissues in Alzheimer's disease through inactivating the PI3K/Akt signaling pathway. J Cell Biochem 2019; 120:18053-18065. [PMID: 31190362 DOI: 10.1002/jcb.29108] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 04/18/2019] [Accepted: 04/29/2019] [Indexed: 12/31/2022]
Abstract
OBJECTIVE The purpose of this study was to elucidate the expression of the long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) in rats with Alzheimer's disease (AD) and to explore its potential mechanisms. METHODS An AD rat model was induced by microinjection of Aβ25-35 . On the first day after successful modeling, pcDNA3.1 plasmid and pcDNA3.1-MEG3 plasmid were continuously infused into the third ventricle through a micro-osmotic pump to interfere with the expression level of MEG3. The spatial learning ability and memory ability, the histopathological changes of hippocampus tissues, the ultrastructure of hippocampal neurons, astrocyte activation as well as the survival and apoptosis of hippocampal neurons in each group was observed. The expression of apoptosis, PI3/Akt signaling pathway-related proteins, glial fibrillary acidic protein, inflammatory factors, malondialdehyde, glutathione-peroxidase, and superoxide dismutase levels were determined. The deposition of amyloid beta (Aβ) in the hippocampus of rats by was observed by Aβ immunohistochemical staining. RESULTS Downregulated MEG3 was detected in the tissues of AD rats. In addition, upregulation of MEG3 contributed to an improvement of spatial learning ability and memory ability, inhibited the pathological injury and its apoptosis of hippocampal neurons, decreased Aβ positive expression, inhibited oxidative stress injury and inflammatory injury as well as the activated astrocytes in AD rats via inactivation of the PI3/Akt pathway. CONCLUSION Our study highlights that upregulation of the lncRNA MEG3 improves cognitive impairment, alleviates neuronal damage, and inhibits activation of astrocytes in hippocampus tissues in AD through inhibiting the PI3K/Akt signaling pathway.
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Affiliation(s)
- Jiping Yi
- Department of Neurology, Translational Medicine Institute, The First People's Hospital of Chenzhou, University of South China, Chenzhou, P.R. China
| | - Bin Chen
- Department of Spinal Surgery, Translational Medicine Institute, The First People's Hospital of Chenzhou, University of South China, Chenzhou, P.R. China
| | - Xiaoxi Yao
- Department of Neurology, Translational Medicine Institute, The First People's Hospital of Chenzhou, University of South China, Chenzhou, P.R. China
| | - Yuanbiao Lei
- Department of Neurology, Translational Medicine Institute, The First People's Hospital of Chenzhou, University of South China, Chenzhou, P.R. China
| | - Fuyong Ou
- Department of Neurology, Translational Medicine Institute, The First People's Hospital of Chenzhou, University of South China, Chenzhou, P.R. China
| | - Fengzhen Huang
- Department of Neurology, Translational Medicine Institute, The First People's Hospital of Chenzhou, University of South China, Chenzhou, P.R. China
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