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Kim H, Lee YY, Kim VN. The biogenesis and regulation of animal microRNAs. Nat Rev Mol Cell Biol 2025; 26:276-296. [PMID: 39702526 DOI: 10.1038/s41580-024-00805-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2024] [Indexed: 12/21/2024]
Abstract
MicroRNAs (miRNAs) are small, yet profoundly influential, non-coding RNAs that base-pair with mRNAs to induce RNA silencing. Although the basic principles of miRNA biogenesis and function have been established, recent breakthroughs have yielded important new insights into the molecular mechanisms of miRNA biogenesis. In this Review, we discuss the metazoan miRNA biogenesis pathway step-by-step, focusing on the key biogenesis machinery, including the Drosha-DGCR8 complex (Microprocessor), exportin-5, Dicer and Argonaute. We also highlight newly identified cis-acting elements and their impact on miRNA maturation, informed by advanced high-throughput and structural studies, and discuss recently discovered mechanisms of clustered miRNA processing, target recognition and target-directed miRNA decay (TDMD). Lastly, we explore multiple regulatory layers of miRNA biogenesis, mediated by RNA-protein interactions, miRNA tailing (uridylation or adenylation) and RNA modifications.
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Affiliation(s)
- Haedong Kim
- Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea
- School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
- Department of Genome Sciences, University of Washington, Seattle, WA, USA
| | - Young-Yoon Lee
- Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea
- School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
| | - V Narry Kim
- Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea.
- School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
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2
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Sumaira S, Vijayarathna S, Hemagirri M, Adnan M, Hassan MI, Patel M, Gupta R, Shanmugapriya, Chen Y, Gopinath SC, Kanwar JR, Sasidharan S. Plant bioactive compounds driven microRNAs (miRNAs): A potential source and novel strategy targeting gene and cancer therapeutics. Noncoding RNA Res 2024; 9:1140-1158. [PMID: 39022680 PMCID: PMC11250886 DOI: 10.1016/j.ncrna.2024.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/21/2024] [Accepted: 06/03/2024] [Indexed: 07/20/2024] Open
Abstract
Irrespective of medical technology improvements, cancer ranks among the leading causes of mortality worldwide. Although numerous cures and treatments exist, creating alternative cancer therapies with fewer adverse side effects is vital. Since ancient times, plant bioactive compounds have already been used as a remedy to heal cancer. These plant bioactive compounds and their anticancer activity can also deregulate the microRNAs (miRNAs) in the cancerous cells. Therefore, the deregulation of miRNAs in cancer cells by plant bioactive compounds and the usage of the related miRNA could be a promising approach for cancer cure, mainly to prevent cancer and overcome chemotherapeutic side effect problems. Hence, this review highlights the function of plant bioactive compounds as an anticancer agent through the underlying mechanism that alters the miRNA expression in cancer cells, ultimately leading to apoptosis. Moreover, this review provides insight into using plant bioactive compounds -driven miRNAs as an anticancer agent to develop miRNA-based cancer gene therapy. They can be the potential resource for gene therapy and novel strategies targeting cancer therapeutics.
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Affiliation(s)
- Sahreen Sumaira
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Soundararajan Vijayarathna
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Manisekaran Hemagirri
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Mohd Adnan
- Department of Biology, College of Science, University of Hail, Hail, P.O. Box 2440, Saudi Arabia
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Mitesh Patel
- Research and Development Cell and Department of Biotechnology, Parul Institute of Applied Sciences, Parul University, Vadodara, 391760, Gujarat, India
| | - Reena Gupta
- Institute of Pharmaceutical Research, Department. Pharmaceutical Research, GLA University, Mathura, India
| | - Shanmugapriya
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Yeng Chen
- Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Subash C.B. Gopinath
- Faculty of Chemical Engineering Technology, Universiti Malaysia Perlis, Perlis, Malaysia
| | - Jagat R. Kanwar
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), 174001, Bilaspur, Himachal Pradesh, India
| | - Sreenivasan Sasidharan
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
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Feng Y, Yang F, Zheng J, Shi L, Xie T, Lin Y, Shi Q. Circular RNA HIPK3 mediates epithelial-mesenchymal transition of retinal pigment epithelial cells by sponging multiple microRNAs. Sci Rep 2024; 14:28872. [PMID: 39572643 PMCID: PMC11582593 DOI: 10.1038/s41598-024-71119-6] [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: 02/20/2024] [Accepted: 08/26/2024] [Indexed: 11/24/2024] Open
Abstract
Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells plays key roles in the pathogenesis of multiple vitreoretinal diseases, leading to profound and permanent vision loss. Circular RNAs (circRNAs) are widespread and functional endogenous RNAs that could regulate gene expression in eukaryotes. The functions of circRNAs in mediating EMT has been reported in several diseases. In the current study, we investigated the role of circRNA HIPK3 (circHIPK3) in EMT process of RPE cells (RPE-EMT). circHIPK3 is one abundant circRNA generated from the second exon of HIPK3 mRNA. We found that circHIPK3 expression was significantly increased in TGF-β1-induced RPE-EMT model. Silencing of circHIPK3 attenuated TGF-β1-induced RPE-EMT process, whereas forced expression of circHIPK3 could trigger EMT in RPE cells. Mechanistically, circHIPK3 regulates RPE-EMT process via sponging multiple microRNAs (miRNAs). This study provides novel insights into the mechanism of RPE-EMT. Targeting circHIPK3 might serve as a therapeutic strategy in RPE-EMT associated vitreoretinal diseases.
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Affiliation(s)
- Yalan Feng
- Department of Ophthalmology, Yixing Eye Hospital, Wuxi School of Medicine, Jiangnan University, Intersection of Hongta Road Kang Ming Road, Yicheng Street, Yixing, 214200, Jiangsu, China
| | - Fan Yang
- Shanghai Eye Diseases Prevention & Treatment Center, Shanghai, China
| | - Jijia Zheng
- Department of Ophthalmology, Hainan Hospital of Chinese PLA General Hospital, Sanya, China
| | - Lijun Shi
- Department of Ophthalmology, Yixing Eye Hospital, Wuxi School of Medicine, Jiangnan University, Intersection of Hongta Road Kang Ming Road, Yicheng Street, Yixing, 214200, Jiangsu, China
| | - Tianhua Xie
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China
| | - Yunzhi Lin
- Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China
| | - Qian Shi
- Department of Ophthalmology, Yixing Eye Hospital, Wuxi School of Medicine, Jiangnan University, Intersection of Hongta Road Kang Ming Road, Yicheng Street, Yixing, 214200, Jiangsu, China.
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4
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Zhang X, Zhu X, Chen L, Fan H, Liu X, Yang N, Wang Y, Duan Y. Functional Identification of miR2119 Targeting ADHs in Modulating Soybean Resistance to Heterodera glycines. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:21461-21474. [PMID: 39311099 PMCID: PMC11450968 DOI: 10.1021/acs.jafc.4c05000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 09/07/2024] [Accepted: 09/17/2024] [Indexed: 10/03/2024]
Abstract
Soybean cyst nematode (SCN, Heterodera glycines) is a sedentary endoparasite nematode that results in severe economic losses in soybean crops. miRNAs play crucial roles in plant responses to nematode. However, the role of miR2119 responding to SCN stress in soybean. Here, we demonstrated that the transcript levels of polycistronic precursors containing miR2119 and miR398a were significantly reduced in soybean upon nematode infection. Promoter of the miR2119-398a precursor analysis was conducted containing a GUS reporter gene. GUS activity assays demonstrated a decrease in miR2119-398a promoter during SCN infection. Overexpression of polycistronic precursor miR2119-398a (OE-premiR2119-398a) and miR2119 precursor (OE-premiR2119) rendered soybean more susceptible to SCN. Conversely, silencing miR2119 (STTM2119) increased soybean resistance against SCN. Furthermore, RNA-seq analysis revealed that miR2119 is involved in many defense signaling pathways. GUS reporter gene assays demonstrated that miR2119 targets GmADH1.1a and GmADH1.1b. Functional analysis indicated that ADHs act as a major role in responding to H. glycines by modulating reactive oxygen species (ROS) levels. Together, the findings reveal a novel mechanism by which the polycistronic precursor miR2119-398a coordinately regulates in response to H. glycines. Additionally, miR2119 becomes an essential element contributing to H. glycines by modulating ADH activity and ROS homeostasis in soybean.
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Affiliation(s)
- Xiaoyu Zhang
- Nematology
Institute of Northern China, Shenyang Agricultural
University, Shenyang 110866, China
- College
of Plant Protection, Shenyang Agricultural
University, Shenyang 110866, China
| | - Xiaofeng Zhu
- Nematology
Institute of Northern China, Shenyang Agricultural
University, Shenyang 110866, China
- College
of Plant Protection, Shenyang Agricultural
University, Shenyang 110866, China
| | - Lijie Chen
- Nematology
Institute of Northern China, Shenyang Agricultural
University, Shenyang 110866, China
- College
of Plant Protection, Shenyang Agricultural
University, Shenyang 110866, China
| | - Haiyan Fan
- Nematology
Institute of Northern China, Shenyang Agricultural
University, Shenyang 110866, China
- College
of Plant Protection, Shenyang Agricultural
University, Shenyang 110866, China
| | - Xiaoyu Liu
- Nematology
Institute of Northern China, Shenyang Agricultural
University, Shenyang 110866, China
- College
of Sciences, Shenyang Agricultural University, Shenyang 110866, China
| | - Ning Yang
- Nematology
Institute of Northern China, Shenyang Agricultural
University, Shenyang 110866, China
- College
of Plant Protection, Shenyang Agricultural
University, Shenyang 110866, China
| | - Yuanyuan Wang
- Nematology
Institute of Northern China, Shenyang Agricultural
University, Shenyang 110866, China
- College
of Biological Science and Technology, Shenyang
Agricultural University, Shenyang 110866, China
| | - Yuxi Duan
- Nematology
Institute of Northern China, Shenyang Agricultural
University, Shenyang 110866, China
- College
of Plant Protection, Shenyang Agricultural
University, Shenyang 110866, China
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Sdeor E, Okada H, Saad R, Ben-Yishay T, Ben-David U. Aneuploidy as a driver of human cancer. Nat Genet 2024; 56:2014-2026. [PMID: 39358600 DOI: 10.1038/s41588-024-01916-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 08/20/2024] [Indexed: 10/04/2024]
Abstract
Aneuploidy, an abnormal chromosome composition, is a major contributor to cancer development and progression and an important determinant of cancer therapeutic responses and clinical outcomes. Despite being recognized as a hallmark of human cancer, the exact role of aneuploidy as a 'driver' of cancer is still largely unknown. Identifying the specific genetic elements that underlie the recurrence of common aneuploidies remains a major challenge of cancer genetics. In this Review, we discuss recurrent aneuploidies and their function as drivers of tumor development. We then delve into the context-dependent identification and functional characterization of the driver genes underlying driver aneuploidies and examine emerging strategies to uncover these driver genes using cancer genomics data and cancer models. Lastly, we explore opportunities for targeting driver aneuploidies in cancer by leveraging the functional consequences of these common genetic alterations.
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Affiliation(s)
- Eran Sdeor
- Department of Human Molecular Genetics and Biochemistry, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Hajime Okada
- Department of Human Molecular Genetics and Biochemistry, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Ron Saad
- Department of Human Molecular Genetics and Biochemistry, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
- The Blavatnik School of Computer Science, Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Tal Ben-Yishay
- Department of Human Molecular Genetics and Biochemistry, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
- The Blavatnik School of Computer Science, Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Uri Ben-David
- Department of Human Molecular Genetics and Biochemistry, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
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6
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Hassanin AAI, Ramos KS. Circulating Exosomal miRNA Profiles in Non-Small Cell Lung Cancers. Cells 2024; 13:1562. [PMID: 39329746 PMCID: PMC11430728 DOI: 10.3390/cells13181562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/08/2024] [Accepted: 09/15/2024] [Indexed: 09/28/2024] Open
Abstract
A growing number of studies have shown that microRNAs (miRNAs) can exert oncogenic or tumor suppressor activities in a variety of cancers, including lung cancer. Given their presence in exosome preparations, microRNA molecules may in fact participate in exosomal intercellular transfers and signaling. In the present study, we examined the profile of 25 circulating exosomal microRNAs in ostensibly healthy controls compared to patients with squamous cell lung cancers (SQCLC) or lung adenocarcinomas (LUAD). Eight miRNAs, namely, miR-21-5p, miR-126-3p, miR-210-3p, miR-221-3p, Let-7b-5p, miR-146a-5p, miR-222-3p, and miR-9-5p, were highly enriched in the cohort and selected for further analyses. All miRNAs were readily detected in non-small cell lung cancer (NSCLC) patients of both sexes at all cancer stages, and their levels in exosomes correlated with the clinicopathological characteristics of tumors. Thus, the presence of these miRNAs in circulating exosomes may contribute to the regulation of oncogenic activity in patients with NSCLC.
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Affiliation(s)
- Abeer A. I. Hassanin
- Center for Genomic and Precision Medicine, Texas A&M Institute of Biosciences and Technology, Texas Medical Center, Houston, TX 77030, USA;
- Department of Animal Wealth Development, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Kenneth S. Ramos
- Center for Genomic and Precision Medicine, Texas A&M Institute of Biosciences and Technology, Texas Medical Center, Houston, TX 77030, USA;
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Leng X, Zhang M, Xu Y, Wang J, Ding N, Yu Y, Sun S, Dai W, Xue X, Li N, Yang Y, Shi Z. Non-coding RNAs as therapeutic targets in cancer and its clinical application. J Pharm Anal 2024; 14:100947. [PMID: 39149142 PMCID: PMC11325817 DOI: 10.1016/j.jpha.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 01/12/2024] [Accepted: 02/01/2024] [Indexed: 08/17/2024] Open
Abstract
Cancer genomics has led to the discovery of numerous oncogenes and tumor suppressor genes that play critical roles in cancer development and progression. Oncogenes promote cell growth and proliferation, whereas tumor suppressor genes inhibit cell growth and division. The dysregulation of these genes can lead to the development of cancer. Recent studies have focused on non-coding RNAs (ncRNAs), including circular RNA (circRNA), long non-coding RNA (lncRNA), and microRNA (miRNA), as therapeutic targets for cancer. In this article, we discuss the oncogenes and tumor suppressor genes of ncRNAs associated with different types of cancer and their potential as therapeutic targets. Here, we highlight the mechanisms of action of these genes and their clinical applications in cancer treatment. Understanding the molecular mechanisms underlying cancer development and identifying specific therapeutic targets are essential steps towards the development of effective cancer treatments.
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Affiliation(s)
- Xuejiao Leng
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Mengyuan Zhang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yujing Xu
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Jingjing Wang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ning Ding
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yancheng Yu
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Shanliang Sun
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Weichen Dai
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Xin Xue
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Nianguang Li
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ye Yang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhihao Shi
- Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, Nanjing, 211198, China
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Yadav P, Tamilselvan R, Mani H, Singh KK. MicroRNA-mediated regulation of nonsense-mediated mRNA decay factors: Insights into microRNA prediction tools and profiling techniques. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2024; 1867:195022. [PMID: 38437914 DOI: 10.1016/j.bbagrm.2024.195022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 02/28/2024] [Accepted: 03/01/2024] [Indexed: 03/06/2024]
Abstract
Nonsense-mediated mRNA decay (NMD) stands out as a prominent RNA surveillance mechanism within eukaryotes, meticulously overseeing both RNA abundance and integrity by eliminating aberrant transcripts. These defective transcripts are discerned through the concerted efforts of translating ribosomes, eukaryotic release factors (eRFs), and trans-acting NMD factors, with Up-Frameshift 3 (UPF3) serving as a noteworthy component. Remarkably, in humans, UPF3 exists in two paralogous forms, UPF3A (UPF3) and UPF3B (UPF3X). Beyond its role in quality control, UPF3 wields significant influence over critical cellular processes, including neural development, synaptic plasticity, and axon guidance. However, the precise regulatory mechanisms governing UPF3 remain elusive. MicroRNAs (miRNAs) emerge as pivotal post-transcriptional gene regulators, exerting substantial impact on diverse pathological and physiological pathways. This comprehensive review encapsulates our current understanding of the intricate regulatory nexus between NMD and miRNAs, with particular emphasis on the essential role played by UPF3B in neurodevelopment. Additionally, we bring out the significance of the 3'-untranslated region (3'-UTR) as the molecular bridge connecting NMD and miRNA-mediated gene regulation. Furthermore, we provide an in-depth exploration of diverse computational tools tailored for the prediction of potential miRNA targets. To complement these computational approaches, we delineate experimental techniques designed to validate predicted miRNA-mRNA interactions, empowering readers with the knowledge necessary to select the most appropriate methodology for their specific research objectives.
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Affiliation(s)
- Priyanka Yadav
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Raja Tamilselvan
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Harita Mani
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India
| | - Kusum Kumari Singh
- Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
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9
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Orang A, Marri S, McKinnon RA, Petersen J, Michael MZ. Restricting Colorectal Cancer Cell Metabolism with Metformin: An Integrated Transcriptomics Study. Cancers (Basel) 2024; 16:2055. [PMID: 38893174 PMCID: PMC11171104 DOI: 10.3390/cancers16112055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/13/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Metformin is a first-line therapy for type 2 diabetes as it disrupts cellular metabolism. Despite the association between metformin and lower cancer incidence, the anti-tumour activity of the drug in colorectal cancer (CRC) is incompletely understood. This study identifies underlying molecular mechanisms by which metformin slows colorectal cancer cell proliferation by investigating metformin-associated microRNA (miRNA) and target gene pairs implicated in signalling pathways. METHODS The present study analysed changes in miRNAs and the coding transcriptome in CRC cells treated with a sublethal dose of metformin, followed by the contextual validation of potential miRNA-target gene pairs. RESULTS Analyses of small RNA and transcriptome sequencing data revealed 104 miRNAs and 1221 mRNAs to be differentially expressed in CRC cells treated with metformin for 72 h. Interaction networks between differentially expressed miRNAs and putative target mRNAs were identified. Differentially expressed genes were mainly implicated in metabolism and signalling processes, such as the PI3K-Akt and MAPK/ERK pathways. Further validation of potential miRNA-target mRNA pairs revealed that metformin induced miR-2110 and miR-132-3p to target PIK3R3 and, consequently, regulate CRC cell proliferation, cell cycle progression and the PI3K-Akt signalling pathway. Metformin also induced miR-222-3p and miR-589-3p, which directly target STMN1 to inhibit CRC cell proliferation and cell cycle progression. CONCLUSIONS This study identified novel changes in the coding transcriptome and small non-coding RNAs associated with metformin treatment of CRC cells. Integration of these datasets highlighted underlying mechanisms by which metformin impedes cell proliferation in CRC. Importantly, it identified the post-transcriptional regulation of specific genes that impact both metabolism and cell proliferation.
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Affiliation(s)
- Ayla Orang
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Shashikanth Marri
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Ross A. McKinnon
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
| | - Janni Petersen
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Nutrition and Metabolism, South Australia Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Michael Z. Michael
- Flinders Health and Medical Research Institute, Flinders University, Bedford Park, SA 5042, Australia; (A.O.); (S.M.); (R.A.M.); (J.P.)
- Department of Gastroenterology and Hepatology, Flinders Medical Centre, Bedford Park, SA 5042, Australia
- Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Bedford Park, SA 5042, Australia
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10
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Ordoñez-Razo RM, Gutierrez-López Y, Araujo-Solis MA, Benitez-King G, Ramírez-Sánchez I, Galicia G. Overexpression of miR-25 Downregulates the Expression of ROBO2 in Idiopathic Intellectual Disability. Int J Mol Sci 2024; 25:3953. [PMID: 38612763 PMCID: PMC11011991 DOI: 10.3390/ijms25073953] [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: 02/27/2024] [Revised: 03/29/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
Idiopathic intellectual disability (IID) encompasses the cases of intellectual disability (ID) without a known cause and represents approximately 50% of all cases. Neural progenitor cells (NPCs) from the olfactory neuroepithelium (NEO) contain the same information as the cells found in the brain, but they are more accessible. Some miRNAs have been identified and associated with ID of known etiology. However, in idiopathic ID, the effect of miRNAs is poorly understood. The aim of this study was to determine the miRNAs regulating the expression of mRNAs that may be involved in development of IID. Expression profiles were obtained using NPC-NEO cells from IID patients and healthy controls by microarray. A total of 796 miRNAs and 28,869 mRNAs were analyzed. Several miRNAs were overexpressed in the IID patients compared to controls. miR-25 had the greatest expression. In silico analysis showed that ROBO2 was the target for miR-25, with the highest specificity and being the most down-regulated. In vitro assay showed an increase of miR-25 expression induced a decrease in ROBO2 expression. In neurodevelopment, ROBO2 plays a crucial role in episodic learning and memory, so its down-regulation, caused by miR-25, could have a fundamental role in the intellectual disability that, until now, has been considered idiopathic.
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Affiliation(s)
- Rosa María Ordoñez-Razo
- Unidad de Investigación Médica en Genética Humana, Hospital de Pediatría “Dr. Silvestre Frenk Freund”, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Mexico City CP 06725, Mexico; (Y.G.-L.); (G.G.)
| | - Yessica Gutierrez-López
- Unidad de Investigación Médica en Genética Humana, Hospital de Pediatría “Dr. Silvestre Frenk Freund”, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Mexico City CP 06725, Mexico; (Y.G.-L.); (G.G.)
| | - María Antonieta Araujo-Solis
- Departamento Clínico de Genética Médica, Hospital de Pediatría “Dr. Silvestre Frenk Freund”, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Mexico City CP 06725, Mexico;
| | - Gloria Benitez-King
- Laboratorio de Neurofarmacología, Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz”, Calzada México Xochimilco No. 101, Col. San Lorenzo Huipulco, Mexico City CP 14370, Mexico;
| | - Israel Ramírez-Sánchez
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City CP 07738, Mexico;
| | - Gabriela Galicia
- Unidad de Investigación Médica en Genética Humana, Hospital de Pediatría “Dr. Silvestre Frenk Freund”, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Av. Cuauhtémoc 330, Col. Doctores, Mexico City CP 06725, Mexico; (Y.G.-L.); (G.G.)
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11
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Jasim SA, Al-Hawary SIS, Kaur I, Ahmad I, Hjazi A, Petkov I, Ali SHJ, Redhee AH, Shuhata Alubiady MH, Al-Ani AM. Critical role of exosome, exosomal non-coding RNAs and non-coding RNAs in head and neck cancer angiogenesis. Pathol Res Pract 2024; 256:155238. [PMID: 38493725 DOI: 10.1016/j.prp.2024.155238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/13/2024] [Accepted: 03/02/2024] [Indexed: 03/19/2024]
Abstract
Head and neck cancer (HNC) refers to the epithelial malignancies of the upper aerodigestive tract. HNCs have a constant yet slow-growing rate with an unsatisfactory overall survival rate globally. The development of new blood vessels from existing blood conduits is regarded as angiogenesis, which is implicated in the growth, progression, and metastasis of cancer. Aberrant angiogenesis is a known contributor to human cancer progression. Representing a promising therapeutic target, the blockade of angiogenesis aids in the reduction of the tumor cells oxygen and nutrient supplies. Despite the promise, the association of existing anti-angiogenic approaches with severe side effects, elevated cancer regrowth rates, and limited survival advantages is incontrovertible. Exosomes appear to have an essential contribution to the support of vascular proliferation, the regulation of tumor growth, tumor invasion, and metastasis, as they are a key mediator of information transfer between cells. In the exocrine region, various types of noncoding RNAs (ncRNAs) identified to be enriched and stable and contribute to the occurrence and progression of cancer. Mounting evidence suggest that exosome-derived ncRNAs are implicated in tumor angiogenesis. In this review, the characteristics of angiogenesis, particularly in HNC, and the impact of ncRNAs on HNC angiogenesis will be outlined. Besides, we aim to provide an insight on the regulatory role of exosomes and exosome-derived ncRNAs in angiogenesis in different types of HNC.
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Affiliation(s)
| | | | - Irwanjot Kaur
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Irfan Ahmad
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
| | - Iliya Petkov
- Medical University - Sofia, Department of Neurology, Sofia, Bulgaria
| | - Saad Hayif Jasim Ali
- Department of medical laboratory, College of Health and Medical Technololgy, Al-Ayen University, Thi-Qar, Iraq
| | - Ahmed Huseen Redhee
- Medical laboratory technique college, the Islamic University, Najaf, Iraq; Medical laboratory technique college, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq; Medical laboratory technique college, the Islamic University of Babylon, Babylon, Iraq
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12
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Wang Y, Tang X, Lu J. Convergent and divergent evolution of microRNA-mediated regulation in metazoans. Biol Rev Camb Philos Soc 2024; 99:525-545. [PMID: 37987240 DOI: 10.1111/brv.13033] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 11/12/2023] [Accepted: 11/14/2023] [Indexed: 11/22/2023]
Abstract
The evolution of microRNAs (miRNAs) has been studied extensively to understand their roles in gene regulation and evolutionary processes. This review focuses on how miRNA-mediated regulation has evolved in bilaterian animals, highlighting both convergent and divergent evolution. Since animals and plants display significant differences in miRNA biogenesis and target recognition, the 'independent origin' hypothesis proposes that miRNA pathways in these groups independently evolved from the RNA interference (RNAi) pathway, leading to modern miRNA repertoires through convergent evolution. However, recent evidence raises the alternative possibility that the miRNA pathway might have already existed in the last common ancestor of eukaryotes, and that the differences in miRNA pathway and miRNA repertoires among animal and plant lineages arise from lineage-specific innovations and losses of miRNA pathways, miRNA acquisition, and loss of miRNAs after eukaryotic divergence. The repertoire of miRNAs has considerably expanded during bilaterian evolution, primarily through de novo creation and duplication processes, generating new miRNAs. Although ancient functionally established miRNAs are rarely lost, many newly emerged miRNAs are transient and lineage specific, following a birth-death evolutionary pattern aligning with the 'out-of-the-testis' and 'transcriptional control' hypotheses. Our focus then shifts to the convergent molecular evolution of miRNAs. We summarize how miRNA clustering and seed mimicry contribute to this phenomenon, and we review how miRNAs from different sources converge to degrade maternal messenger RNAs (mRNAs) during animal development. Additionally, we describe how miRNAs evolve across species due to changes in sequence, seed shifting, arm switching, and spatiotemporal expression patterns, which can result in variations in target sites among orthologous miRNAs across distant strains or species. We also provide a summary of the current understanding regarding how the target sites of orthologous miRNAs can vary across strains or distantly related species. Although many paralogous miRNAs retain their seed or mature sequences after duplication, alterations can occur in the seed or mature sequences or expression patterns of paralogous miRNAs, leading to functional diversification. We discuss our current understanding of the functional divergence between duplicated miRNAs, and illustrate how the functional diversification of duplicated miRNAs impacts target site evolution. By investigating these topics, we aim to enhance our current understanding of the functions and evolutionary dynamics of miRNAs. Additionally, we shed light on the existing challenges in miRNA evolutionary studies, particularly the complexity of deciphering the role of miRNA-mediated regulatory network evolution in shaping gene expression divergence and phenotypic differences among species.
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Affiliation(s)
- Yirong Wang
- Bioinformatics Center, College of Biology, Hunan University, Changsha, 410082, China
| | - Xiaolu Tang
- State Key Laboratory of Protein and Plant Gene Research, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, 100871, China
| | - Jian Lu
- State Key Laboratory of Protein and Plant Gene Research, Center for Bioinformatics, School of Life Sciences, Peking University, Beijing, 100871, China
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13
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Chen D, Hagen SJ, Boyce M, Zhao CM. Neuroendocrine mechanism of gastric acid secretion: Historical perspectives and recent developments in physiology and pharmacology. J Neuroendocrinol 2023; 35:e13305. [PMID: 37317882 PMCID: PMC10656367 DOI: 10.1111/jne.13305] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 04/24/2023] [Accepted: 05/10/2023] [Indexed: 06/16/2023]
Abstract
The physiology of gastric acid secretion is one of the earliest subjects in medical literature and has been continuously studied since 1833. Starting with the notion that neural stimulation alone drives acid secretion, progress in understanding the physiology and pathophysiology of this process has led to the development of therapeutic strategies for patients with acid-related diseases. For instance, understanding the physiology of parietal cells led to the developments of histamine 2 receptor blockers, proton pump inhibitors (PPIs), and recently, potassium-competitive acid blockers. Furthermore, understanding the physiology and pathophysiology of gastrin has led to the development of gastrin/CCK2 receptor (CCK2 R) antagonists. The need for refinement of existing drugs in patients have led to second and third generation drugs with better efficacy at blocking acid secretion. Further understanding of the mechanism of acid secretion by gene targeting in mice has enabled us to dissect the unique role for each regulator to leverage and justify the development of new targeted therapeutics for acid-related disorders. Further research on the mechanism of stimulation of gastric acid secretion and the physiological significances of gastric acidity in gut microbiome is needed in the future.
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Affiliation(s)
- Duan Chen
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Susan J Hagen
- Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | | | - Chun-Mei Zhao
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
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14
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Asberger J, Berner K, Bicker A, Metz M, Jäger M, Weiß D, Kreutz C, Juhasz-Böss I, Mayer S, Ge I, Erbes T. In Vitro microRNA Expression Profile Alterations under CDK4/6 Therapy in Breast Cancer. Biomedicines 2023; 11:2705. [PMID: 37893081 PMCID: PMC10604872 DOI: 10.3390/biomedicines11102705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/16/2023] [Accepted: 09/27/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Breast cancer is the most common type of cancer worldwide. Cyclin-dependent kinase inhibition is one of the backbones of metastatic breast cancer therapy. However, there are a significant number of therapy failures. This study evaluates the biomarker potential of microRNAs for the prediction of a therapy response under cyclin-dependent kinase inhibition. METHODS This study comprises the analysis of intracellular and extracellular microRNA-expression-level alterations of 56 microRNAs under palbociclib mono as well as combination therapy with letrozole. Breast cancer cell lines BT-474, MCF-7 and HS-578T were analyzed using qPCR. RESULTS A palbociclib-induced microRNA signature could be detected intracellularly as well as extracellularly. Intracellular miR-10a, miR-15b, miR-21, miR-23a and miR-23c were constantly regulated in all three cell lines, whereas let-7b, let-7d, miR-15a, miR-17, miR-18a, miR-20a, miR-191 and miR301a_3p were regulated only in hormone-receptor-positive cells. Extracellular miR-100, miR-10b and miR-182 were constantly regulated across all cell lines, whereas miR-17 was regulated only in hormone-receptor-positive cells. CONCLUSIONS Because they are secreted and significantly upregulated in the microenvironment of tumor cells, miRs-100, -10b and -182 are promising circulating biomarkers that can be used to predict or detect therapy responses under CDK inhibition. MiR-10a, miR-15b, miR-21, miR-23a and miR-23c are potential tissue-based biomarkers.
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Affiliation(s)
- Jasmin Asberger
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Kai Berner
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Anna Bicker
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Obstetrics and Gynecology, St. Josefs-Hospital Wiesbaden, 65189 Wiesbaden, Germany
| | - Marius Metz
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Markus Jäger
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Daniela Weiß
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Clemens Kreutz
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Institute of Medical Biometry and Statistics, Medical Center – University of Freiburg, 79104 Freiburg, Germany
| | - Ingolf Juhasz-Böss
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Sebastian Mayer
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Gynaecology and Obstetrics, Hospital Krumbach, 86381 Krumbach, Germany
| | - Isabell Ge
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Obstetrics and Gynaecology, University Hospital of Basel, 4056 Basel, Switzerland
| | - Thalia Erbes
- Department of Obstetrics and Gynecology, Medical Center—University Hospital Freiburg, 79106 Freiburg, Germany
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Department of Gynaecology and Obstetrics, Diako Mannheim, 68135 Mannheim, Germany
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15
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Wang Y, Su X, Leung GHD, Ren B, Zhang Q, Xiong Z, Zhou J, Yang L, Lu G, Chan WY, Ren L. Circulating microRNAs as diagnostic biomarkers for ischemic stroke: evidence from comprehensive analysis and real-world validation. Int J Med Sci 2023; 20:1009-1023. [PMID: 37484808 PMCID: PMC10357437 DOI: 10.7150/ijms.83963] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 05/16/2023] [Indexed: 07/25/2023] Open
Abstract
Ischemic stroke (IS) is the majority of strokes which remain the second leading cause of deaths in the last two decades. Circulating microRNAs (miRNAs) have been suggested as potential diagnostic and therapeutic tools for IS by previous studies analyzing their differential expression. However, inconclusive and controversial conclusions of these results have to be addressed. In this study, comprehensive analysis and real-world validation were performed to assess the associations between circulating miRNAs and IS. 29 studies with 112 miRNAs were extracted after manual selection and filtering, 12 differentially expressed miRNAs were obtained from our results of meta-analysis. These miRNAs were evaluated in 20 IS patients, compared to 20 healthy subjects. 4 miRNAs (hsa-let-7e-5p, hsa-miR-124-3p, hsa-miR-17-5p, hsa-miR-185-5p) exhibited the significant expression level in IS patient plasma samples. Pathway and biological process enrichment analysis for the target genes of the 4 validated miRNAs identified cellular senescence and neuroinflammation as key post-IS response pathways. The results of our analyses closely correlated with the pathogenesis and implicated pathways observed in IS subjects suggested by the literature, which may provide aid in the development of circulating diagnostic or therapeutic targets for IS patients.
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Affiliation(s)
- Yang Wang
- Department of Neurology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518000, China
| | - Xianwei Su
- Research and Development Unit, Shenzhen GenDo Medical Technology Co., Ltd., Dapeng, Shenzhen 518000, China
| | | | - Bohua Ren
- Department of Epidemiology and Biostatistics, School of Public Health, Guangdong Medical University, Dongguan 523808, China
- Faculty of Education, Health and Wellbeing, University of Wolverhampton, Wolverhampton WV1 1QU, UK
| | - Qiang Zhang
- Department of Neurology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518000, China
| | - Zhiqiang Xiong
- SDIVF R&D Centre, 209,12W, HKSTP, Shatin, Hong Kong, China
| | - Jingye Zhou
- Research and Development Unit, Shenzhen GenDo Medical Technology Co., Ltd., Dapeng, Shenzhen 518000, China
| | - Ling Yang
- Department of Neurology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518000, China
| | - Gang Lu
- CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Wai-Yee Chan
- CUHK-SDU Joint Laboratory on Reproductive Genetics, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lijie Ren
- Department of Neurology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518000, China
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16
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Hu Q, Huang T. Regulation of the Cell Cycle by ncRNAs Affects the Efficiency of CDK4/6 Inhibition. Int J Mol Sci 2023; 24:ijms24108939. [PMID: 37240281 DOI: 10.3390/ijms24108939] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Cyclin-dependent kinases (CDKs) regulate cell division at multiple levels. Aberrant proliferation induced by abnormal cell cycle is a hallmark of cancer. Over the past few decades, several drugs that inhibit CDK activity have been created to stop the development of cancer cells. The third generation of selective CDK4/6 inhibition has proceeded into clinical trials for a range of cancers and is quickly becoming the backbone of contemporary cancer therapy. Non-coding RNAs, or ncRNAs, do not encode proteins. Many studies have demonstrated the involvement of ncRNAs in the regulation of the cell cycle and their abnormal expression in cancer. By interacting with important cell cycle regulators, preclinical studies have demonstrated that ncRNAs may decrease or increase the treatment outcome of CDK4/6 inhibition. As a result, cell cycle-associated ncRNAs may act as predictors of CDK4/6 inhibition efficacy and perhaps present novel candidates for tumor therapy and diagnosis.
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Affiliation(s)
- Qingyi Hu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tao Huang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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17
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Yu Y, Meng LL, Chen XY, Fan HN, Chen M, Zhang J, Zhu JS. m 6A reader YTHDF3 is associated with clinical prognosis, related RNA signatures and immunosuppression in gastric cancer. Cell Signal 2023; 108:110699. [PMID: 37149073 DOI: 10.1016/j.cellsig.2023.110699] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 04/24/2023] [Accepted: 05/01/2023] [Indexed: 05/08/2023]
Abstract
BACKGROUND YTHDF3 as a N6-methyladenosine (m6A) reader participates in the development and progression of multiple cancer types, however, the prognosis, molecular biology and immune infiltration of YTHDF3 in gastric cancer (GC) have not been investigated. METHODS The YTHDF3 expression profile and clinicopathological parameters of stomach adenocarcinoma (STAD) were downloaded from TCGA. The online websites and databases such as GEPIA2, cBioPortal, UALCAN, ImmuCellAl, xCell, TISIDB, GSCA were utilized for analysis of the association of YTHDF3 with STAD, including clinical prognosis, WGCNA and LASSO Cox regression analysis. Further functional assays such as RT-qPCR, Western blot, immunohistochemistry (IHC), immunofluorescence (IF), CCK-8, colony formation, EdU and Transwell assays were performed to determine the role of YTHDF3 in GC. RESULTS We found that YTHDF3 was upregulated in STAD tissue samples ascribed to its copy number amplification and associated with poor prognosis in patients with STAD. GO and KEGG analyses showed that YTHDF3-related differential genes were predominantly enriched in the proliferation, metabolism and immune signaling pathways. Knockdown of YTHDF3 repressed the growth and invasion of GC cells by inhibition of PI3K/AKT signaling. We then identified YTHDF3-related lncRNAs, miRNAs and mRNAs, and constructed their prognostic signatures in patients with STAD. Moreover, YTHDF3 associated with tumor immune infiltration such as CD8+ T cells, macrophages, Tregs, MHC molecules and chemokines, upregulated PD-L1 and CXCL1 and exerted a response to the immunotherapy in GC. CONCLUSIONS YTHDF3 upregulation indicates poor prognosis and promotes GC cell growth and invasion by activating PI3K/AKT pathway and regulating immune microenvironment. The established YTHDF3-related signatures highlight the association of YTHDF3 with the clinical prognosis and immune cell infiltration in GC.
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Affiliation(s)
- Yi Yu
- Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Li-Li Meng
- Department of Pathology, Zhongshan Hospital, Fudan University, China
| | - Xiao-Yu Chen
- Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Hui-Ning Fan
- Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Ming Chen
- Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
| | - Jing Zhang
- Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
| | - Jin-Shui Zhu
- Department of Gastroenterology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.
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18
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Vilimova M, Pfeffer S. Post-transcriptional regulation of polycistronic microRNAs. WILEY INTERDISCIPLINARY REVIEWS. RNA 2023; 14:e1749. [PMID: 35702737 DOI: 10.1002/wrna.1749] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/20/2022] [Accepted: 05/24/2022] [Indexed: 02/02/2023]
Abstract
An important proportion of microRNA (miRNA) genes tend to lie close to each other within animal genomes. Such genomic organization is generally referred to as miRNA clusters. Even though many miRNA clusters have been greatly studied, most attention has been usually focused on functional impacts of clustered miRNA co-expression. However, there is also another compelling aspect about these miRNA clusters, their polycistronic nature. Being transcribed on a single RNA precursor, polycistronic miRNAs benefit from common transcriptional regulation allowing their coordinated expression. And yet, numerous reports have revealed striking discrepancies in the accumulation of mature miRNAs produced from the same cluster. Indeed, the larger polycistronic transcripts can act as platforms providing unforeseen post-transcriptional regulatory mechanisms controlling individual miRNA processing, thus leading to differential miRNA expression, and sometimes even challenging the general assumption that polycistronic miRNAs are co-expressed. In this review, we aim to address the current knowledge about how miRNA polycistrons are post-transcriptionally regulated. In particular, we will focus on the mechanisms occurring at the level of the primary transcript, which are highly relevant for individual miRNA processing and as such have a direct repercussion on miRNA function within the cell. This article is categorized under: RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes.
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Affiliation(s)
- Monika Vilimova
- Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, Strasbourg, France
| | - Sébastien Pfeffer
- Architecture et Réactivité de l'ARN, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, Strasbourg, France
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19
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Ste-Croix DT, Bélanger RR, Mimee B. Characterization of microRNAs in the cyst nematode Heterodera glycines identifies possible candidates involved in cross-kingdom interactions with its host Glycine max. RNA Biol 2023; 20:614-628. [PMID: 37599428 PMCID: PMC10443972 DOI: 10.1080/15476286.2023.2244790] [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] [Revised: 07/21/2023] [Accepted: 07/31/2023] [Indexed: 08/22/2023] Open
Abstract
The soybean cyst nematode (SCN - Heterodera glycines) is one of the most damaging pests to the cultivated soybean worldwide. Using a wide array of stylet-secreted effector proteins, this nematode can restructure its host cells into a complex and highly active feeding structure called the syncytium. Tight regulation of these proteins is thought to be essential to the successful formation of this syncytium. To date, multiple mechanisms have been proposed to regulate the expression of these proteins including through post-transcriptional regulation. MicroRNAs (miRNAs) are a class of small, roughly 22-nucleotide-long, non-coding RNA shown to regulate gene expression through its interaction with the 3' untranslated region of genes. These same small RNAs have also been hypothesized to be able to cross over kingdom barriers and regulate genes in other species in a process called cross-kingdom interactions. In this study, we characterized the miRNome of the SCN via sequencing of small-RNAs isolated from whole nematodes and exosomes representing all developmental stages. We identified 121 miRNA loci encoding 96 distinct miRNA families including multiple lineage- and species-specific candidates. Using a combination of plant- and animal-specific miRNA target predictors, we generated a unique repertoire of miRNA:mRNA interacting partners in the nematode and its host plant leading to the identification of a set of nine probable cross-kingdom miRNA candidates.
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Affiliation(s)
- Dave T. Ste-Croix
- Saint-Jean-Sur-Richelieu Research and Development Centre, Agriculture and Agri-Food Canada, Saint-Jean-Sur-Richelieu, Canada
- Département de Phytologie, Université Laval, Québec, Canada
| | - Richard R. Bélanger
- Département de Phytologie, Université Laval, Québec, Canada
- Centre de Recherche et d’Innovation sur les Végétaux (CRIV), Université Laval, Québec, Canada
| | - Benjamin Mimee
- Saint-Jean-Sur-Richelieu Research and Development Centre, Agriculture and Agri-Food Canada, Saint-Jean-Sur-Richelieu, Canada
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20
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Partial Disturbance of Microprocessor Function in Human Stem Cells Carrying a Heterozygous Mutation in the DGCR8 Gene. Genes (Basel) 2022; 13:genes13111925. [DOI: 10.3390/genes13111925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/14/2022] [Accepted: 10/20/2022] [Indexed: 11/04/2022] Open
Abstract
Maturation of microRNAs (miRNAs) begins by the “Microprocessor” complex, containing the Drosha endonuclease and its partner protein, "DiGeorge Syndrome Critical Region 8" (DGCR8). Although the main function of the two proteins is to coordinate the first step of precursor miRNAs formation, several studies revealed their miRNA-independent functions in other RNA-related pathways (e.g., in snoRNA decay) or, for the DGCR8, the role in tissue development. To investigate the specific roles of DGCR8 in various cellular pathways, we previously established a human embryonic stem-cell (hESC) line carrying a monoallelic DGCR8 mutation by using the CRISPR-Cas9 system. In this study, we genetically characterized single-cell originated progenies of the cell line and showed that DGCR8 heterozygous mutation results in only a modest effect on the mRNA level but a significant decrease at the protein level. Self-renewal and trilineage differentiation capacity of these hESCs were not affected by the mutation. However, partial disturbance of the Microprocessor function could be revealed in pri-miRNA processing along the human chromosome 19 miRNA cluster in several clones. With all these studies, we can demonstrate that the mutant hESC line is a good model to study not only miRNA-related but also other “noncanonical” functions of the DGCR8 protein.
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21
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Pandey M, Luhur A, Sokol NS, Chawla G. Molecular Dissection of a Conserved Cluster of miRNAs Identifies Critical Structural Determinants That Mediate Differential Processing. Front Cell Dev Biol 2022; 10:909212. [PMID: 35784477 PMCID: PMC9247461 DOI: 10.3389/fcell.2022.909212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/25/2022] [Indexed: 11/13/2022] Open
Abstract
Differential processing is a hallmark of clustered microRNAs (miRNAs) and the role of position and order of miRNAs in a cluster together with the contribution of stem-base and terminal loops has not been explored extensively within the context of a polycistronic transcript. To elucidate the structural attributes of a polycistronic transcript that contribute towards the differences in efficiencies of processing of the co-transcribed miRNAs, we constructed a series of chimeric variants of Drosophila let-7-Complex that encodes three evolutionary conserved and differentially expressed miRNAs (miR-100, let-7 and miR-125) and examined the expression and biological activity of the encoded miRNAs. The kinetic effects of Drosha and Dicer processing on the chimeric precursors were examined by in vitro processing assays. Our results highlight the importance of stem-base and terminal loop sequences in differential expression of polycistronic miRNAs and provide evidence that processing of a particular miRNA in a polycistronic transcript is in part determined by the kinetics of processing of adjacent miRNAs in the same cluster. Overall, this analysis provides specific guidelines for achieving differential expression of a particular miRNA in a cluster by structurally induced changes in primary miRNA (pri-miRNA) sequences.
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Affiliation(s)
- Manish Pandey
- RNA Biology Laboratory, Regional Centre for Biotechnology, Faridabad, India
| | - Arthur Luhur
- Department of Biology, Indiana University, Bloomington, IN, United States
| | - Nicholas S. Sokol
- Department of Biology, Indiana University, Bloomington, IN, United States
| | - Geetanjali Chawla
- RNA Biology Laboratory, Regional Centre for Biotechnology, Faridabad, India
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22
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Tian W, Pang X, Luan F. Diagnosis value of miR-181, miR-652, and CA72-4 for gastric cancer. J Clin Lab Anal 2022; 36:e24411. [PMID: 35446997 PMCID: PMC9169223 DOI: 10.1002/jcla.24411] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 12/01/2022] Open
Abstract
PURPOSE To find a useful disease marker for early diagnosis of gastric cancer, we tried to explore the expression of serum miR-181, miR-652, and carbohydrate antigen 72-4 (CA72-4). PATIENTS AND METHODS According to clinical pathologic stages, 112 patients with gastric cancer were divided into early gastric cancer group (n = 60) and advanced gastric cancer group (n = 52), stage I-II (n = 65), and stage III-IV (n = 47). Another 50 cases of gastric benign lesions and 40 healthy controls were also selected. Real-time quantitative PCR together with chemiluminescence were applied to detect expression levels. ROC curve was applied to judge their diagnostic efficiency. Pearson's correlation analysis was put into use to investigate the relevance of three indicators. RESULTS Compared with benign lesions group and control group, significantly higher expression levels were found in patients of gastric cancer (all p < 0.001). Similarly, compared with early gastric cancer group, significantly higher expression levels were found in advanced gastric cancer group (all p < 0.001). The same result was also found in stage III-IV (all p < 0.001). The best cutoff values were 0.93, 2.38, and 16.94 U/ml, respectively. The area under the curve (0.917, 95%CI: 0.856-0.975) of the three combined diagnosis of early gastric cancer was the largest, and its sensitivity and specificity were 92.5% and 86.8%. And miR-181 and miR-652 were positively correlated with CA72-4 (r = 0.772, p < 0.001, r = 0.853, p < 0.001). CONCLUSION Serum miR-181, miR-652, and CA72-4 are closely linked to the occurrence and development of gastric cancer. Combination of three indicators has diagnostic value for early gastric cancer.
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Affiliation(s)
- Wenyan Tian
- Department of GastroenterologyFirst Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
| | - Xueqin Pang
- Department of GastroenterologyFirst Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
| | - Fujuan Luan
- Department of GastroenterologyFirst Affiliated Hospital of Soochow UniversitySuzhouPeople’s Republic of China
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23
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Sgubin M, Pegoraro S, Pellarin I, Ros G, Sgarra R, Piazza S, Baldassarre G, Belletti B, Manfioletti G. HMGA1 positively regulates the microtubule-destabilizing protein stathmin promoting motility in TNBC cells and decreasing tumour sensitivity to paclitaxel. Cell Death Dis 2022; 13:429. [PMID: 35504904 PMCID: PMC9065117 DOI: 10.1038/s41419-022-04843-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 03/30/2022] [Accepted: 04/06/2022] [Indexed: 12/14/2022]
Abstract
High Mobility Group A1 (HMGA1) is an architectural chromatin factor involved in the regulation of gene expression and a master regulator in Triple Negative Breast Cancer (TNBC). In TNBC, HMGA1 is overexpressed and coordinates a gene network that controls cellular processes involved in tumour development, progression, and metastasis formation. Here, we find that the expression of HMGA1 and of the microtubule-destabilizing protein stathmin correlates in breast cancer (BC) patients. We demonstrate that HMGA1 depletion leads to a downregulation of stathmin expression and activity on microtubules resulting in decreased TNBC cell motility. We show that this pathway is mediated by the cyclin-dependent kinase inhibitor p27kip1 (p27). Indeed, the silencing of HMGA1 expression in TNBC cells results both in an increased p27 protein stability and p27-stathmin binding. When the expression of both HMGA1 and p27 is silenced, we observe a significant rescue in cell motility. These data, obtained in cellular models, were validated in BC patients. In fact, we find that patients with high levels of both HMGA1 and stathmin and low levels of p27 have a statistically significant lower survival probability in terms of relapse-free survival (RFS) and distant metastasis-free survival (DMFS) with respect to the patient group with low HMGA1, low stathmin, and high p27 expression levels. Finally, we show in an in vivo xenograft model that depletion of HMGA1 chemo-sensitizes tumour cells to paclitaxel, a drug that is commonly used in TNBC treatments. This study unveils a new interaction among HMGA1, p27, and stathmin that is critical in BC cell migration. Moreover, our data suggest that taxol-based treatments may be more effective in reducing the tumour burden when tumour cells express low levels of HMGA1.
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Affiliation(s)
- Michela Sgubin
- grid.5133.40000 0001 1941 4308Department of Life Sciences, University of Trieste, Trieste, Italy ,grid.418321.d0000 0004 1757 9741Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute, Aviano, Italy
| | - Silvia Pegoraro
- grid.5133.40000 0001 1941 4308Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Ilenia Pellarin
- grid.418321.d0000 0004 1757 9741Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute, Aviano, Italy
| | - Gloria Ros
- grid.5133.40000 0001 1941 4308Department of Life Sciences, University of Trieste, Trieste, Italy ,grid.5970.b0000 0004 1762 9868Present Address: International School for Advanced Studies (SISSA), Area of Neuroscience Trieste, Trieste, Italy
| | - Riccardo Sgarra
- grid.5133.40000 0001 1941 4308Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Silvano Piazza
- grid.425196.d0000 0004 1759 4810International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, Trieste, Italy
| | - Gustavo Baldassarre
- grid.418321.d0000 0004 1757 9741Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute, Aviano, Italy
| | - Barbara Belletti
- grid.418321.d0000 0004 1757 9741Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, National Cancer Institute, Aviano, Italy
| | - Guidalberto Manfioletti
- grid.5133.40000 0001 1941 4308Department of Life Sciences, University of Trieste, Trieste, Italy
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24
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Hafstað V, Søkilde R, Häkkinen J, Larsson M, Vallon-Christersson J, Rovira C, Persson H. Regulatory networks and 5' partner usage of miRNA host gene fusions in breast cancer. Int J Cancer 2022; 151:95-106. [PMID: 35182081 PMCID: PMC9303785 DOI: 10.1002/ijc.33972] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 02/07/2022] [Accepted: 02/10/2022] [Indexed: 11/12/2022]
Abstract
Genomic rearrangements in cancer cells can create gene fusions where the juxtaposition of two different genes leads to the production of chimeric proteins or altered gene expression through promoter‐swapping. We have previously shown that fusion transcripts involving microRNA (miRNA) host genes contribute to deregulation of miRNA expression regardless of the protein‐coding potential of these transcripts. Many different genes can also be used as 5′ partners by a miRNA host gene in what we named recurrent miRNA‐convergent fusions. Here, we have explored the properties of 5′ partners in fusion transcripts that involve miRNA hosts in breast tumours from The Cancer Genome Atlas (TCGA). We hypothesised that firstly, 5′ partner genes should belong to pathways and transcriptional programmes that reflect the tumour phenotype and secondly, there should be a selection for fusion events that shape miRNA expression to benefit the tumour cell through the known hallmarks of cancer. We found that the set of 5′ partners in miRNA host fusions is non‐random, with overrepresentation of highly expressed genes in pathways active in cancer including epithelial‐to‐mesenchymal transition, translational regulation and oestrogen signalling. Furthermore, many miRNAs were upregulated in samples with host gene fusions, including established oncogenic miRNAs such as mir‐21 and the mir‐106b~mir‐93~mir‐25 cluster. To the list of mechanisms for deregulation of miRNA expression, we have added fusion transcripts that change the promoter region. We propose that this adds material for genetic selection and tumour evolution in cancer cells and that miRNA host fusions can act as tumour ‘drivers’.
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Affiliation(s)
- Völundur Hafstað
- Lund University Cancer Centre, Faculty of Medicine, Department of Clinical Sciences Lund, Oncology, Lund, Sweden
| | - Rolf Søkilde
- Lund University Cancer Centre, Faculty of Medicine, Department of Clinical Sciences Lund, Oncology, Lund, Sweden
| | - Jari Häkkinen
- Lund University Cancer Centre, Faculty of Medicine, Department of Clinical Sciences Lund, Oncology, Lund, Sweden
| | - Malin Larsson
- Department of Physics, Chemistry and Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Linköping University, Linköping, Sweden
| | - Johan Vallon-Christersson
- Lund University Cancer Centre, Faculty of Medicine, Department of Clinical Sciences Lund, Oncology, Lund, Sweden
| | - Carlos Rovira
- Lund University Cancer Centre, Faculty of Medicine, Department of Clinical Sciences Lund, Oncology, Lund, Sweden
| | - Helena Persson
- Lund University Cancer Centre, Faculty of Medicine, Department of Clinical Sciences Lund, Oncology, Lund, Sweden
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25
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Asadi-Samani M, Mahmoudian-Sani MR. Association between extract of Euphorbia szovitsii and expression level of microRNAs in MDA-MB-231 cell line. Mol Biol Rep 2022; 49:3531-3537. [PMID: 35132492 DOI: 10.1007/s11033-022-07193-8] [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: 11/09/2021] [Accepted: 01/25/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND The miRNAs have been shown to be involved in breast cancer. The aim of the present research was to evaluate the impacts of extract from Euphorbia szovitsii Fisch & C.A. Mey on the expression level of microRNAs in triple-negative breast cancer (MDA-MB-231) cell line. METHODS AND RESULT The alterations in the expression level of miRNAs in MDA-MB-231 cell line exposed to the extract of E. szovitsii were determined exploiting qRT-PCR technique. The expression of MDA-MB-231 cell microRNAs including miR-15, miR-16, miR-21, miR-29, miR-34a, miR-146b, miR-151, miR-155, miR-181b, miR-221, miR-222, and Let-7 was evaluated at 24 and 48 h after treatment with the E. szovitsii extract. The treatment of MDA-MB-231 cells with E. szovitsii caused a significant elevation in the expression of miR-155, miR-146b (P < 0.05), miR-16, miR-21, miR-151 (P < 0.01), and miR-34a (P < 0.001) after 24 h, and also miR-155, Let-7 (P < 0.05), miR-15, miR-29, miR-151 (P < 0. 01), miR-146b and miR-34a (P<0.001) after 48 h. CONCLUSIONS The qRT-PCR findings at 24 and 48 h after treatment revealed that the MDA-MB-231 cell line in the presence of E. szovitsii extract showed an alteration in the expression profile of miRNAs implicated in the induction of cell proliferation, apoptosis and migration. These results may be helpful in determining the anticancer activity of E. szovitsii in MDA-MB-231 cell line.
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Affiliation(s)
- Majid Asadi-Samani
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad-Reza Mahmoudian-Sani
- Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Clinical Research Development Unit, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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26
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Liu Z, Huang Y, Han Z, Shen Z, Yu S, Wang T, Dong Z, Kang M. Exosome-mediated miR-25/miR-203 as a potential biomarker for esophageal squamous cell carcinoma: improving early diagnosis and revealing malignancy. Transl Cancer Res 2022; 10:5174-5182. [PMID: 35116367 PMCID: PMC8799214 DOI: 10.21037/tcr-21-1123] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 10/24/2021] [Indexed: 01/23/2023]
Abstract
Background Esophageal squamous cell carcinoma (ESCC) is the leading cause of cancer death in men and women worldwide. The poor prognosis and rapid increase in ESCC incidence highlight the need to promote early detection and prediction. Identifying key molecular targets involved in ESCC monitoring and progression is critical for ESCC patients. Methods This study examined miR-25/miR-203 as a biomarker for ESCC patients. Real-time quantitative polymerase chain reaction (PCR) was used to detect miR-25/miR-203 expression levels in tissues and serum exosomes, and MiR-25/miR-203 upregulation was confirmed in ESCC. Results We found that the miR-25/miR-203 ratio in cancer tissues from 36 ESCC patients was significantly enhanced compared with that in adjacent tissues. Moreover, the serum level of miR-25/miR-203 in 57 ESCC patients was higher than that in 31 healthy volunteers. Intriguingly, in 38 ESCC patients, the level of miR-25/miR-203 decreased significantly after surgery. Using ROC curve statistical analysis, we found that each group of miR-25/miR-203 had obvious sensitivity and high specificity. The miR-25/miR-203 relationship with the clinicopathological features of ESCC patients was also analyzed. MiR-25/miR-203 was significantly associated with the ESCC TNM-stage and lymph node metastasis, which predicts the prognosis of ESCC and reflects tumor progression. Conclusions This study highlights the feasibility of using exosome-mediated miR-25/miR-203 as a vital noninvasive biomarker for the detection and treatment monitoring of ESCC.
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Affiliation(s)
- Zhun Liu
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Ying Huang
- Department of Infusion, Fujian Medical University Union Hospital, Fuzhou, China
| | - Ziyang Han
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Zhimin Shen
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Shaobin Yu
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Tao Wang
- Jiangsu Engineering Research Center for Tumor Molecular Diagnosis, Suzhou, China
| | - Zhaonan Dong
- Jiangsu Engineering Research Center for Tumor Molecular Diagnosis, Suzhou, China
| | - Mingqiang Kang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.,Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China
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27
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Tan W, Li Z, Xia W, Zhu J, Fan R. miR-221-3p regulates hepatocellular carcinoma cell proliferation, migration and invasion via targeting LIFR. Ann Hepatol 2022; 27 Suppl 1:100567. [PMID: 34699986 DOI: 10.1016/j.aohep.2021.100567] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/03/2021] [Accepted: 03/25/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Hepatocellular carcinoma (HCC) is one of the most common and fatal cancers in the world. This study aims to investigate the mechanism by which miR-221-3p regulates HCC cell proliferation, migration and invasion, so as to provide a new idea for targeted therapy towards HCC. MATERIALS AND METHODS Expression quantification data including mature miRNA and mRNA were accessed from TCGA-LIHC dataset, and matched clinical information was obtained as well, which helped identify the miRNA of interest. Thereafter, effect of the miRNA on HCC cell biological functions was assessed with a series of in vitro experiments, such as qRT-PCR, MTT, wound healing assay and Transwell. To gain more insight into the mechanism of the miRNA in HCC, bioinformatics method was conducted to predict downstream target gene. The potential targeting relationship between the miRNA and the predicted mRNA was validated by dual-luciferase reporter assay. Western blot was performed to test protein expression. RESULTS MiR-221-3p identified by differential expression analysis was found to be significantly elevated in HCC tissue. Overexpressing miR-221-3p noticeably enhanced HCC cell proliferative, migratory and invasive abilities. Leukemia inhibitory factor receptor (LIFR), confirmed as a downstream target of miR-221-3p in HCC by dual-luciferase reporter assay, was poorly expressed in HCC tissue and cells. Additionally, the expression of LIFR was decreased following the targeted binding between miR-221-3p and LIFR 3'-UTR, while increasing the expression of LIFR attenuated the promoting effect of miR-221-3p on HCC cells. CONCLUSION MiR-221-3p is an oncogene in HCC cells, and it exerts its role in HCC cell viability and motility via targeting LIFR.
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Affiliation(s)
- Wei Tan
- Department of Hepatobiliary and Pancreatic Surgery, Lishui Municipal Central Hospital, Lishui, Zhejiang province, China
| | - Zhuokai Li
- Department of Hepatobiliary and Pancreatic Surgery, Lishui Municipal Central Hospital, Lishui, Zhejiang province, China
| | - Weifen Xia
- Department of Hepatobiliary and Pancreatic Surgery, Lishui Municipal Central Hospital, Lishui, Zhejiang province, China
| | - Jinde Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Lishui Municipal Central Hospital, Lishui, Zhejiang province, China
| | - Rengen Fan
- Department of General Surgery, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, The First people's Hospital of Yancheng, 166 West Yulong Road, Yancheng 224000, Jiangsu province, China.
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28
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Yildiz MT, Tutar L, Giritlioğlu NI, Bayram B, Tutar Y. MicroRNAs and Heat Shock Proteins in Breast Cancer Biology. Methods Mol Biol 2022; 2257:293-310. [PMID: 34432285 DOI: 10.1007/978-1-0716-1170-8_15] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Breast cancer has five major immune types; luminal A, luminal B, HER2, Basal-like, and normal-like. Cells produce a family of protein called heat shock proteins (Hsps) in response to exposure to thermal and other proteotoxic stresses play essential roles in cancer metabolism and this large family shows a diverse set of Hsp involvement in different breast cancer immune types. Recently, Hsp members categorized according to their immune type roles. Hsp family consists of several subtypes formed by molecular weight; Hsp70, Hsp90, Hsp100, Hsp40, Hsp60, and small molecule Hsps. Cancer cells employ Hsps as survival factors since most of these proteins prevent apoptosis. Several studies monitored Hsp roles in breast cancer cells and reported Hsp27 involvement in drug resistance, Hsp70 in tumor cell transformation-progression, and interaction with p53. Furthermore, the association of Hsp90 with steroid receptors and signaling proteins in patients with breast cancer directed research to focus on Hsp-based treatments. miRNAs are known to play key roles in all types of cancer that are upregulated or downregulated in cancer which respectively referred to as oncogenes (oncomirs) or tumor suppressors. Expression profiles of miRNAs may be used to classify, diagnose, and predict different cancer types. It is clear that miRNAs play regulatory roles in gene expression and this work reveals miRNA correlation to Hsp depending on specific breast cancer immune types. Deregulation of specific Hsp genes in breast cancer subtypes allows for identification of new targets for drug design and cancer treatment. Here, we performed miRNA network analysis by recruiting Hsp genes detected in breast cancer subtypes and reviewed some of the miRNAs related to aforementioned Hsp genes.
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Affiliation(s)
- Mehmet Taha Yildiz
- Division of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey
| | - Lütfi Tutar
- Department of Molecular Biology and Genetics, Faculty of Art and Sciences, Kırşehir Ahi Evran University, Kırşehir, Turkey
| | - Nazlı Irmak Giritlioğlu
- Department of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey
| | - Banu Bayram
- Department of Nutrition and Dietetics, Hamidiye Faculty of Health Sciences, University of Health Sciences, Istanbul, Turkey
| | - Yusuf Tutar
- Division of Molecular Medicine, Hamidiye Institute of Health Sciences, University of Health Sciences, Istanbul, Turkey.
- Division of Biochemistry, Department of Basic Pharmaceutical Sciences, Hamidiye Faculty of Pharmacy, University of Health Sciences, Istanbul, Turkey.
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Hu J, Zhang J, Yu M, Liu Z, Zou Y, Hong L, Zhang T, Sun J, Zheng M, Zhu X, Wang Z, Liu S. Circulating miR-221/222 reduces CD4+ T cells by inhibiting CD4 expression in colorectal cancer. Acta Biochim Biophys Sin (Shanghai) 2021; 53:1367-1376. [PMID: 34357372 DOI: 10.1093/abbs/gmab106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 07/14/2021] [Accepted: 07/22/2021] [Indexed: 11/13/2022] Open
Abstract
Many patients with cancers have low levels of CD4+ in their peripheral blood. However, the molecular mechanism is still unclear. Here, we found that the blood levels of miR-221 and miR-222 were dramatically increased in patients with colorectal cancer (CRC), and both circulating miR-211 and miR-222 served as sensitive diagnostic markers with an area under the curve of 0.8790 and 0.9148, respectively. Transfection of either miR-221 or miR-222 resulted in the reduction of the surface CD4 antigen level but not the surface CD8 antigen level. The luciferase reporter assay showed that miR-221/222 directly regulated CD4 expression in human primary T cells. These data showed that miR-221/222 levels were upregulated in the blood of patients with CRC and that the expression of CD4 in human primary T cells was inhibited by miR-221/222. These findings provide a novel strategy for modulating the number of CD4+ T cells in the blood and further adjusting the microenvironment suitable for immunotherapy.
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Affiliation(s)
- Jiajia Hu
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China
| | - Jiawei Zhang
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
| | - Meng Yu
- State Key Laboratory for Mechanical Behavior of Materials, Xi’an Jiaotong University, Xi’an 710061, China
| | - Zukai Liu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
| | - Yan Zou
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
| | - Liwen Hong
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Tianyu Zhang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Jing Sun
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Minhua Zheng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Xuekai Zhu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China
| | - Zhengting Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Sanhong Liu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Prediction of Blood miRNA-mRNA Regulatory Network in Gastric Cancer. Rep Biochem Mol Biol 2021; 10:243-256. [PMID: 34604414 DOI: 10.52547/rbmb.10.2.243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 10/13/2020] [Indexed: 01/15/2023]
Abstract
Background The aim of the study was to suggest a high specific and sensitive blood biomarker for early GC diagnosis. Methods the expression data of miRNAs and mRNAs were collected from the blood samples of the GC patients based on literature mining. Bioinformatics tools and databases (PANTHER, TargetScan, miRTarBase, miRDB, STRING, and Cytoscape) were used to predict the regulatory relationship. Subsequently, expression level of the selected miRNA was evaluated in the blood samples of gastritis patients to recognize the common miRNA between the GC and gastritis patients. Results Analysis of 40 target genes by MCODE (installed in Cytoscape software) indicated 4 hub genes (WWP1, SKP2, KLHL42, and FBXO11) as a significant cluster in the PPI network related to miR-21, with Node Score Cutoff: 0.2, Degree Cutoff: 2 and K-Core: 2. In addition, the miRNA RT-qPCR results showed that, the expression level of miR-21 was significantly higher in gastritis group compared to the healthy group (p< 0.05). Conclusion the present study clearly demonstrated the increasing level of blood miR-21 among the gastritis patients infected by H. pylori. Therefore, the altered miRNAs, especially overexpression of onco-miRs, may identify a potential link between miRNAs and pathogenesis of the H. pylori-related complications.
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Lal M, Ansari AH, Agrawal A, Mukhopadhyay A. Diagnostic and Prognostic Potential of MiR-379/656 MicroRNA Cluster in Molecular Subtypes of Breast Cancer. J Clin Med 2021; 10:jcm10184071. [PMID: 34575183 PMCID: PMC8467195 DOI: 10.3390/jcm10184071] [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: 05/08/2021] [Revised: 08/24/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023] Open
Abstract
Introduction: Breast cancer is the most frequently diagnosed cancer globally and is one of the most important contributors to cancer-related deaths. Earlier diagnosis is known to reduce mortality, and better biomarkers are needed. MiRNA clusters often co-express and target mRNAs in a coordinated fashion, perturbing entire pathways; they thus merit further exploration for diagnostic or prognostic use. MiR-379/656, at chromosome 14q32, is the second largest miRNA cluster in the human genome and implicated in various malignancies including glioblastoma, melanoma, gastrointestinal tumors and ovarian cancer highlighting its potential importance. In this study, we focus on the diagnostic and prognostic potentials of MiR-379/656 in breast cancer and its molecular subtypes. Materials and Methods: We analyzed miRNA and mRNA next generation sequencing data from 903 primary tumors and 90 normal controls (source: The Cancer Genome Atlas). The differential expression profile between tumor and normal was analyzed using DeSEQ2. Penalized logistic regression modelling (lasso regression) was used to assess the predictive potential of MiR-379/656 expression for tumor and normal samples. The association between MiR-379/656 expression and overall patient survival was studied using Cox Proportional-Hazard Model. The target mRNAs (validated) of MiR-379/656 were annotated via pathway enrichment analysis to understand the biological significance of the cluster in breast cancer. Results: The differential expression analysis for 1390 miRNAs (miRnome) revealed 310 upregulated (22.3%) and 176 downregulated (12.66%) miRNAs in breast cancer patients compared with controls. For MiR-379/656, 32 miRNAs (32/42; 76%) were downregulated. The MiR-379/656 cluster was found to be the most differentially expressed cluster in the human genome (p < 10−30). The Basal and Luminal B subtypes showed at least 83% (35/42) of the miRNAs to be downregulated. The binomial model prioritized 15 miRNAs, which distinguished breast cancer patients from controls with 99.15 ± 0.58% sensitivity and 77.78 ± 5.24% specificity. Overall, the Basal and Luminal B showed the most effective predictive power with respect to the 15 prioritized miRNAs at MiR-379/656 cluster. The decreased expression of MiR-379/656 was found to be associated with poorer clinical outcome in Basal and Luminal B subtypes, increasing tumor stage and tumor size/extent, and overall patient survival. Pathway enrichment for the validated targets of MiR-379/656 was significant for cancer-related pathways, especially DNA repair, transcriptional regulation by p53 and cell cycle checkpoints (adjusted p-value < 0.05). Conclusions: Genome informatics analysis of high throughput data for MiR-379/656 cluster has shown that a subset of 15 miRNAs from MiR-379/656 cluster can be used for the diagnostic and prognostic purpose of breast cancer and its subtypes—especially in Basal and Luminal B.
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Affiliation(s)
- Megha Lal
- Genomics & Molecular Medicine Unit, CSIR-Institute of Genomics & Integrative Biology, Delhi 110025, India; (M.L.); (A.H.A.); (A.A.)
- Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India
| | - Asgar Hussain Ansari
- Genomics & Molecular Medicine Unit, CSIR-Institute of Genomics & Integrative Biology, Delhi 110025, India; (M.L.); (A.H.A.); (A.A.)
- Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India
| | - Anurag Agrawal
- Genomics & Molecular Medicine Unit, CSIR-Institute of Genomics & Integrative Biology, Delhi 110025, India; (M.L.); (A.H.A.); (A.A.)
- Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India
| | - Arijit Mukhopadhyay
- Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh 201002, India
- Biomedical Research Centre, Translational Medicine Unit, University of Salford, Manchester M5 4WT, UK
- Correspondence: ; Tel.: +44-0161-295-8129
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Wang P, Zhou Y, Richards AM. Effective tools for RNA-derived therapeutics: siRNA interference or miRNA mimicry. Theranostics 2021; 11:8771-8796. [PMID: 34522211 PMCID: PMC8419061 DOI: 10.7150/thno.62642] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/30/2021] [Indexed: 12/18/2022] Open
Abstract
The approval of the first small interfering RNA (siRNA) drug Patisiran by FDA in 2018 marks a new era of RNA interference (RNAi) therapeutics. MicroRNAs (miRNA), an important post-transcriptional gene regulator, are also the subject of both basic research and clinical trials. Both siRNA and miRNA mimics are ~21 nucleotides RNA duplexes inducing mRNA silencing. Given the well performance of siRNA, researchers ask whether miRNA mimics are unnecessary or developed siRNA technology can pave the way for the emergence of miRNA mimic drugs. Through comprehensive comparison of siRNA and miRNA, we focus on (1) the common features and lessons learnt from the success of siRNAs; (2) the unique characteristics of miRNA that potentially offer additional therapeutic advantages and opportunities; (3) key areas of ongoing research that will contribute to clinical application of miRNA mimics. In conclusion, miRNA mimics have unique properties and advantages which cannot be fully matched by siRNA in clinical applications. MiRNAs are endogenous molecules and the gene silencing effects of miRNA mimics can be regulated or buffered to ameliorate or eliminate off-target effects. An in-depth understanding of the differences between siRNA and miRNA mimics will facilitate the development of miRNA mimic drugs.
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Affiliation(s)
- Peipei Wang
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore
- Department of Medicine, National University Health System, 119228 Singapore
| | - Yue Zhou
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore
- Department of Medicine, National University Health System, 119228 Singapore
| | - Arthur M. Richards
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, 117599 Singapore
- Department of Medicine, National University Health System, 119228 Singapore
- Christchurch Heart Institute, Department of Medicine, University of Otago Christchurch, New Zealand
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Pita I, Libânio D, Dias F, Teixeira AL, Nogueira I, Medeiros R, Dinis-Ribeiro M, Pimentel-Nunes P. Original Article: MicroRNA Dysregulation in the Gastric Carcinogenesis Cascade: Can We Anticipate Its Role in Individualized Care? Pathobiology 2021; 88:338-350. [PMID: 34274936 DOI: 10.1159/000515548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 03/01/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Gastric carcinogenesis progresses from normal mucosa, atrophic/metaplastic gastritis, and dysplasia to adenocarcinoma. MicroRNAs (miRNAs) regulate DNA expression and have been implicated; however, their role is not fully established. AIMS The aim of this study was to characterize plasma and tissue expression of several miRNAs in gastric carcinogenesis stages. METHODS Single-center cross-sectional study in 64 patients: 19 controls (normal mucosa); 15 with extensive atrophic/metaplastic gastritis; and 30 with early gastric neoplasia (EGN). Seven miRNAs (miR-21, miR-146a, miR-181b, miR-370, miR-375, miR 181b, and miR-490) were quantified by real time-qPCR in peripheral blood and endoscopic biopsy samples. RESULTS We found a significant upregulation of miR-181b, miR-490, and miR-21 in the EGN mucosa (overexpression 2-14-times higher than controls). We observed a significant underexpression of miR-146a and miR-370 in atrophic/metaplastic gastritis (86 and 66% decrease, p = 0.008 and p = 0.001) and in EGN (89 and 62% reduction, p = 0.034 and p = 0.032) compared with controls. There were no differences between lesions and nonneoplastic mucosa and no dysregulation of plasma miRNAs. CONCLUSION We found significant dysregulation of 5 miRNAs in gastric carcinogenesis, suggesting a tumor suppressor role for miR-146a and miR-370 and oncogenic potential for miR-21, miR-181, and miR-490. These changes happen diffusely in the gastric mucosa, suggesting a high-risk field defect, which may influence these patients' surveillance.
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Affiliation(s)
- Inês Pita
- Gastroenterology Department, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
| | - Diogo Libânio
- Gastroenterology Department, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
- MEDCIDS - Department of Community Medicine, Health Information and Decision of the Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
| | - Francisca Dias
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
- Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal
| | - Ana Luísa Teixeira
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
| | - Inês Nogueira
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
- Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal
- Research Department of the Portuguese League Against Cancer Regional Nucleus of the North (LPCC-NRN), Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
- Research Department of the Portuguese League Against Cancer Regional Nucleus of the North (LPCC-NRN), Porto, Portugal
- Faculty of Medicine, University of Porto (FMUP), Porto, Portugal
- Biomedical Research Center (CEBIMED), Faculty of Health Sciences of the Fernando Pessoa University (UFP), Porto, Portugal
| | - Mário Dinis-Ribeiro
- Gastroenterology Department, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
- MEDCIDS - Department of Community Medicine, Health Information and Decision of the Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
| | - Pedro Pimentel-Nunes
- Gastroenterology Department, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
- MEDCIDS - Department of Community Medicine, Health Information and Decision of the Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
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Jiang Y, Gai Y, Long Y, Liu Q, Liu C, Zhang Y, Lan X. Application and Evaluation of [ 99mTc]-Labeled Peptide Nucleic Acid Targeting MicroRNA-155 in Breast Cancer Imaging. Mol Imaging 2021; 19:1536012120916124. [PMID: 32559121 PMCID: PMC7307583 DOI: 10.1177/1536012120916124] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
It has been reported that dysregulation of microRNA-155 expression and function is associated with tumorigenesis, growth, tumor subtypes, invasion, and poor survival rates. Peptide nucleic acid (PNA), an artificially synthesized nucleic acid mimic, has been applied for molecular diagnosis. In this study, a PNA sequence that undergoes complementary binding to miR-155 was labeled with 99mTc to evaluate whether the tracer could visualize the expression of miR-155 in breast cancer. Both antisense PNA (anti-PNA, fully complementary bound to human mature miR-155, referred to as “anti-PNA-155”) and mismatched PNA (referred to as “mis-PNA”) single strands containing 23-mer were synthesized. The relative expression of miR-155 in MCF-7 cells and tumors was higher than that in MDA-MB-231 cells and tumors. Single-photon emission computed tomography (SPECT) scan showed that radioactivity mainly accumulated in kidney. MCF-7 tumors, but not MDA-MB-231 tumors, were clearly visualized after [99mTc]anti-PNA-155 injection. MCF-7 tumors were less visible when coinjected with 100-fold excess of anti-PNA-155 or injected with [99mTc]mis-PNA, which suggested specific binding. Biodistribution study results were consistent with SPECT imaging. We successfully demonstrated that [99mTc]anti-PNA-155 could visualize miR-155 expression in vivo, suggesting it may be a promising probe applied in breast cancer.
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Affiliation(s)
- Yaqun Jiang
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yongkang Gai
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yu Long
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Qingyao Liu
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Chunbao Liu
- Department of Nuclear Medicine, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongxue Zhang
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Xiaoli Lan
- Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
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MiRNA Expression in Neuroendocrine Neoplasms of Frequent Localizations. Noncoding RNA 2021; 7:ncrna7030038. [PMID: 34202122 PMCID: PMC8293323 DOI: 10.3390/ncrna7030038] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/20/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022] Open
Abstract
Neuroendocrine neoplasms (NEN) are infrequent malignant tumors of a neuroendocrine nature that arise in various organs. They occur most frequently in the lungs, intestines, stomach and pancreas. Molecular diagnostics and prognosis of NEN development are highly relevant. The role of clinical biomarkers can be played by microRNAs (miRNAs). This work is devoted to the analysis of data on miRNA expression in NENs. For the first time, a search for specificity or a community of their functional characteristics in different types of NEN was carried out. Their properties as biomarkers were also analyzed. To date, more than 100 miRNAs have been characterized as differentially expressed and significant for the development of NEN tumors. Only about 10% of the studied miRNAs are expressed in several types of NEN; differential expression of the remaining 90% was found only in tumors of specific localizations. A significant number of miRNAs have been identified as potential biomarkers. However, only a few miRNAs have values that characterized their quality as markers. The analysis demonstrates the predominant specific expression of miRNA in each studied type of NEN. This indicates that miRNA’s functional features are predominantly influenced by the tissue in which they are formed.
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Gallardo Martin E, Cousillas Castiñeiras A. Vitamin D modulation and microRNAs in gastric cancer: prognostic and therapeutic role. Transl Cancer Res 2021; 10:3111-3127. [PMID: 35116620 PMCID: PMC8797897 DOI: 10.21037/tcr-20-2813] [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: 08/30/2020] [Accepted: 10/10/2020] [Indexed: 12/11/2022]
Abstract
Gastric adenocarcinoma arises after a complex interaction between the host and environmental factors. Tumor location and TNM are the tools that currently guide treatment decisions. Surgery is the only curative treatment, but relapse is common. After relapse or advanced staged disease survival is poor and systemic treatment has modestly improved survival. An association between sun exposure, vitamin D status and gastric cancer (GC) incidence and mortality has been reported. The molecular differences of the histological subtypes and the new molecular classifications account for the great heterogeneity of this disease and are the basis for the discovery of new therapeutic targets. New prognostic and predictive factors are essential and microRNAs (miRNAs) are endogenous small non-coding RNA molecules with a great potential for diagnosis, prognosis and treatment of cancer. There are hundreds of miRNAs with altered expression in tumor gastric tissue when compared to normal gastric tissue. Many of these miRNAs are associated with clinicopathological variables and survival in patients with GC. Furthermore, the expression of some of these miRNAs with prognostic importance in CG is influenced by vitamin D and others are mediators of some of the actions of this vitamin. This review aims to update the evidence on several miRNAs with prognostic value and therapeutic potential in GC, whose expression may be influenced by vitamin D or may regulate vitamin D signaling.
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Affiliation(s)
- Elena Gallardo Martin
- Medical Oncology Department in Complejo Hospitalario Universitario de Pontevedra, University Hospital of Pontevedra, CP 36001 Pontevedra, Spain
| | - Antia Cousillas Castiñeiras
- Medical Oncology Department in Complejo Hospitalario Universitario de Pontevedra, University Hospital of Pontevedra, CP 36001 Pontevedra, Spain
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Fasoulakis Z, Daskalakis G, Diakosavvas M, Papapanagiotou I, Theodora M, Bourazan A, Alatzidou D, Pagkalos A, Kontomanolis EN. MicroRNAs Determining Carcinogenesis by Regulating Oncogenes and Tumor Suppressor Genes During Cell Cycle. Microrna 2021; 9:82-92. [PMID: 31538910 PMCID: PMC7366009 DOI: 10.2174/2211536608666190919161849] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 05/21/2019] [Accepted: 08/03/2019] [Indexed: 02/06/2023]
Abstract
AIM To provide a review considering microRNAs regulating oncogenes and tumor suppressor genes during the different stages of cell cycle, controlling carcinogenesis. METHODS The role of microRNAs involved as oncogenes' and tumor suppressor genes' regulators in cancer was searched in the relevant available literature in MEDLINE, including terms such as "microRNA", "oncogenes", "tumor suppressor genes", "metastasis", "cancer" and others. RESULTS MicroRNAs determine the expression levels of multiple cell cycle regulators, such as cyclins, cyclin dependent kinases and other major cell cycle activators including retinoblastoma 1 (RB- 1) and p53, resulting in alteration and promotion/inhibition of the cell cycle. CONCLUSION MicroRNAs are proven to have a key role in cancer pathophysiology by altering the expression profile of different regulator proteins during cell division cycle and DNA replication. Thus, by acting as oncogenes and tumor suppressor genes, they can either promote or inhibit cancer development and formation, revealing their innovative role as biomarkers and therapeutic tools.
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Affiliation(s)
- Zacharias Fasoulakis
- Department of Obstetrics and Gynecology, Democritus University of Thrace, Alexandroupolis, Greece
| | - George Daskalakis
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Michail Diakosavvas
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioannis Papapanagiotou
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Marianna Theodora
- 1st Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens, Athens, Greece
| | - Arzou Bourazan
- Department of Obstetrics and Gynecology, Democritus University of Thrace, Alexandroupolis, Greece
| | - Dimitra Alatzidou
- Department of Obstetrics and Gynecology, Democritus University of Thrace, Alexandroupolis, Greece
| | - Athanasios Pagkalos
- Department of Obstetrics and Gynecology, General Hospital of Xanthi, Thrace, Greece
| | - Emmanuel N Kontomanolis
- Department of Obstetrics and Gynecology, Democritus University of Thrace, Alexandroupolis, Greece
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Zi Y, Zhang Y, Wu Y, Zhang L, Yang R, Huang Y. Downregulation of microRNA‑25‑3p inhibits the proliferation and promotes the apoptosis of multiple myeloma cells via targeting the PTEN/PI3K/AKT signaling pathway. Int J Mol Med 2021; 47:8. [PMID: 33448321 PMCID: PMC7834966 DOI: 10.3892/ijmm.2020.4841] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 12/04/2020] [Indexed: 12/30/2022] Open
Abstract
Numerous studies have confirmed that microRNAs (miRNAs or miRs) have important roles in cancer biogenesis and development including multiple myeloma (MM). MicroRNA-25-3p (miR-25-3p) has been proven to promote cancer progression, whereas its functions in MM has not yet been reported, at least to the best of our knowledge. Therefore, the present study aimed to investigate the function of miR-25-3p in MM and to identify the potential underlying mechanistic pathway. Herein, it was found that miR-25-3p expression was significantly increased in MM tissues and cell lines. The upregulation of miR-25-3p was closely associated with anemia, renal function impairment international staging system (ISS) staging and Durie-Salmon (D-S) staging. A high level of miR-25-3p was predictive of a poor prognosis of patients with MM. In vitro, the knockdown of miR-25-3p suppressed the proliferation and promoted the apoptosis of RPMI-8226 and U266 cells, while the overexpression of miR-25-3p exerted opposite effects. In addition, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a well-known tumor suppressor, was confirmed as a target of miR-25-3p in MM cells. Moreover, it was found that the PTEN expression levels were decreased, and inversely correlated with miR-25-3p expression levels in MM tissues. Further analyses revealed that the overexpression of PTEN exerted effects similar to those of miR-25-3p knockdown, whereas the knockdown of PTEN partially abolished the effects of miR-25-3p inhibitor on MM cells. Accompanied by PTEN induction, miR-25-3p promoted PI3K/AKT signaling pathway activation in MM cells. Collectively, these findings demonstrate critical roles for miR-25-3p in the pathogenesis of MM, and suggest that miR-25-3p may serve as a novel prognostic biomarker and therapeutic target of MM.
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Affiliation(s)
- Youmei Zi
- Department of Hematology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Yingzi Zhang
- Department of Blood Transfusion, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Yanwei Wu
- Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Lina Zhang
- Central Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Ru Yang
- Henan Key Laboratory of Neurorestoratology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Yan Huang
- Department of Hematology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
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Integrative p53, micro-RNA and Cathepsin Protease Co-Regulatory Expression Networks in Cancer. Cancers (Basel) 2020; 12:cancers12113454. [PMID: 33233599 PMCID: PMC7699684 DOI: 10.3390/cancers12113454] [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: 10/12/2020] [Revised: 11/05/2020] [Accepted: 11/18/2020] [Indexed: 12/12/2022] Open
Abstract
Simple Summary This article describes an emerging area of significant interest in cancer and cell death and the relationships shared by these through the transcriptional regulation of cathepsin protease genes by micro-RNAs that are connected to p53 activation. While it has been demonstrated that the p53 protein can directly regulate some cathepsin genes and the expression of their upstream regulatory micro-RNAs, very little is known about what input the p53 isoform proteins may have in regulating this relationship. Herein, we draw attention to this important regulatory aspect in the context of describing mechanisms that are being established for the micro-RNA regulation of cathepsin protease genes and their collective use in diagnostic or prognostic assays. Abstract As the direct regulatory role of p53 and some of its isoform proteins are becoming established in modulating gene expression in cancer research, another aspect of this mode of gene regulation that has captured significant interest over the years is the mechanistic interplay between p53 and micro-RNA transcriptional regulation. The input of this into modulating gene expression for some of the cathepsin family members has been viewed as carrying noticeable importance based on their biological effects during normal cellular homeostasis and cancer progression. While this area is still in its infancy in relation to general cathepsin gene regulation, we review the current p53-regulated micro-RNAs that are generating significant interest through their regulation of cathepsin proteases, thereby strengthening the link between activated p53 forms and cathepsin gene regulation. Additionally, we extend our understanding of this developing relationship to how such micro-RNAs are being utilized as diagnostic or prognostic tools and highlight their future uses in conjunction with cathepsin gene expression as potential biomarkers within a clinical setting.
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An G, Lu F, Huang S, Bai J, He L, Liu Y, Hou L. Effects of miR‑93 on epithelial‑to‑mesenchymal transition and vasculogenic mimicry in triple‑negative breast cancer cells. Mol Med Rep 2020; 23:30. [PMID: 33179106 PMCID: PMC7673331 DOI: 10.3892/mmr.2020.11668] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 10/08/2020] [Indexed: 11/06/2022] Open
Abstract
Triple‑negative breast cancer (TNBC) is characterized by strong invasiveness, frequent local recurrence and distant metastasis, with poor prognosis. According to tumor angiogenesis theory, tumor cells can obtain blood supply not only by fusing with host blood vessels, but also by constructing a new vascular system through angiogenesis, so as to continuously obtain nutrients and oxygen supply; this is called vasculogenic mimicry (VM). In our previous study, differential expression profiles of miRNAs were examined with gene chip in TNBC and corresponding paracancer tissues, which demonstrated significant up‑regulation of microRNA (miR)‑93. Bioinformatics found that the target genes of miR‑93 were associated with cell proliferation, invasion and migration. The present study investigated the association between miR‑93, epithelial‑to‑mesenchymal transition (EMT) and VM formation in TNBC cell lines. The results indicated that miR‑93 depletion suppressed MDA‑MB‑231 cell viability, invasion and migration (P<0.001). In addition, knockdown of miR‑93 significantly upregulated the expression levels of EMT‑associated genes such as E‑cadherin and occludin, but downregulated the expression levels of vimentin and N‑cadherin in MDA‑MB‑231 cells. VM formation assay showed a significant decrease in microtubule‑forming ability of cells following miR‑93 knockdown, which was associated with the occurrence of EMT, suggesting that miR‑93 may promote the formation of VM via EMT and may be a therapeutic target for the treatment of TNBC.
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Affiliation(s)
- Gaili An
- Department of Clinical Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Feng Lu
- Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Shangke Huang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China
| | - Jun Bai
- Department of Clinical Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Li He
- Department of Clinical Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Yi Liu
- Department of Clinical Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Lei Hou
- Department of Clinical Oncology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
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Yin L, Cai W, Liang Y, Yao J, Wang X, Shen J. In situ self-assembly of Au-antimiR-155 nanocomplexes mediates TLR3-dependent apoptosis in hepatocellular carcinoma cells. Aging (Albany NY) 2020; 13:241-261. [PMID: 33173017 PMCID: PMC7834998 DOI: 10.18632/aging.103799] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023]
Abstract
MicroRNA 155 (miRNA-155) is frequently dysregulated in hepatocellular carcinoma (HCC) and other cancer types. Toll-like receptor 3 (TLR3), a putative miR-155 target, plays a key role in liver pathophysiology, and its downregulation in HCC cells is associated with apoptosis evasion and poor outcomes. Herein, we examined the ability of in situ self-assembled Au-antimiR-155 nanocomplexes (Au-antimiRNA NCs) to activate TLR3 signaling in HCC cells. Gene expression analysis confirmed an inverse relationship between miR-155 and TLR3 expression in HCC samples, and marked upregulation of miR-155 was observed in HCC cells but not in normal L02 hepatocytes. RNA immunoprecipitation confirmed physical interaction between miR-155 and TLR3, while negative regulation of TLR3 expression by miR-155 was demonstrated by luciferase reporter assays. Au-antimiR-155 NCs were self-assembled within HepG2 HCC cells, but not within control L02 cells. They efficiently silenced miR-155, thereby inhibiting proliferation and migration and inducing apoptosis in HepG2 cells. Molecular analyses suggested these effects are secondary to TLR3 signaling mediating NF-κB transcription, caspase-8 activation, and interleukin-1β (IL-1β) release. Our results provide a basis for future studies examining the in vivo applicability of this novel Au-antimiRNA NCs delivery system to halt HCC progression by activating pro-apoptotic TLR3 signaling.
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Affiliation(s)
- Liang Yin
- Department of Endocrinology, Shunde Hospital of Southern Medical University, The First People's Hospital of Shunde Foshan, Shunde 528300, P. R. China
| | - Weijuan Cai
- State Key Laboratory of Bioelectronics, Chien-Shiung Wu Lab, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
| | - Yongqian Liang
- Department of Endocrinology, Shunde Hospital of Southern Medical University, The First People's Hospital of Shunde Foshan, Shunde 528300, P. R. China
| | - Jie Yao
- Central Laboratory, Shunde Hospital of Southern Medical University, The First People's Hospital of Shunde Foshan, Shunde 528300, P. R. China
| | - Xuemei Wang
- State Key Laboratory of Bioelectronics, Chien-Shiung Wu Lab, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, P. R. China
| | - Jie Shen
- Department of Endocrinology, Shunde Hospital of Southern Medical University, The First People's Hospital of Shunde Foshan, Shunde 528300, P. R. China
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Fóthi Á, Biró O, Erdei Z, Apáti Á, Orbán TI. Tissue-specific and transcription-dependent mechanisms regulate primary microRNA processing efficiency of the human chromosome 19 MicroRNA cluster. RNA Biol 2020; 18:1170-1180. [PMID: 33052778 DOI: 10.1080/15476286.2020.1836457] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
One of the longest human microRNA (miRNA) clusters is located on chromosome 19 (C19MC), containing 46 miRNA genes, which were considered to be expressed simultaneously and at similar levels from a common long noncoding transcript. Investigating the two tissue types where C19MC is exclusively expressed, we could show that there is a tissue-specific and chromosomal position-dependent decrease in mature miRNA levels towards the 3' end of the cluster in embryonic stem cells but not in placenta. Although C19MC transcription level is significantly lower in stem cells, this gradual decrease is not present at the primary miRNA levels, indicating that a difference in posttranscriptional processing could explain this observation. By depleting Drosha, the nuclease component of the Microprocessor complex, we could further enhance the positional decrease in stem cells, demonstrating that a tissue-specific, local availability of the Microprocessor complex could lie behind the phenomenon. Moreover, we could describe a tissue-specific promoter being exclusively active in placenta, and the epigenetic mark analysis suggested the presence of several putative enhancer sequences in this region. Performing specific chromatin immunoprecipitation followed by quantitative real-time PCR experiments we could show a strong association of Drosha with selected enhancer regions in placenta, but not in embryonic stem cells. These enhancers could provide explanation for a more efficient co-transcriptional recruitment of the Microprocessor, and therefore a more efficient processing of pri-miRNAs throughout the cluster in placenta. Our results point towards a new model where tissue-specific, posttranscriptional 'fine-tuning' can differentiate among miRNAs that are expressed simultaneously from a common precursor.
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Affiliation(s)
- Ábel Fóthi
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Orsolya Biró
- Department of Obstetrics and Gynaecology, Semmelweis University, Budapest, Hungary
| | - Zsuzsa Erdei
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Ágota Apáti
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Tamás I Orbán
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
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43
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Creff J, Besson A. Functional Versatility of the CDK Inhibitor p57 Kip2. Front Cell Dev Biol 2020; 8:584590. [PMID: 33117811 PMCID: PMC7575724 DOI: 10.3389/fcell.2020.584590] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 09/17/2020] [Indexed: 12/19/2022] Open
Abstract
The cyclin/CDK inhibitor p57Kip2 belongs to the Cip/Kip family, with p21Cip1 and p27Kip1, and is the least studied member of the family. Unlike the other family members, p57Kip2 has a unique role during embryogenesis and is the only CDK inhibitor required for embryonic development. p57Kip2 is encoded by the imprinted gene CDKN1C, which is the gene most frequently silenced or mutated in the genetic disorder Beckwith-Wiedemann syndrome (BWS), characterized by multiple developmental anomalies. Although initially identified as a cell cycle inhibitor based on its homology to other Cip/Kip family proteins, multiple novel functions have been ascribed to p57Kip2 in recent years that participate in the control of various cellular processes, including apoptosis, migration and transcription. Here, we will review our current knowledge on p57Kip2 structure, regulation, and its diverse functions during development and homeostasis, as well as its potential implication in the development of various pathologies, including cancer.
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Affiliation(s)
- Justine Creff
- Centre National de la Recherche Scientifique, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Centre de Biologie Intégrative, Université de Toulouse, Toulouse, France
| | - Arnaud Besson
- Centre National de la Recherche Scientifique, Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération, Centre de Biologie Intégrative, Université de Toulouse, Toulouse, France
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Zhe Q, Yiu WC, Yip HY, Nong W, Yu CWC, Lee IHT, Wong AYP, Wong NWY, Cheung FKM, Chan TF, Lau KF, Zhong S, Chu KH, Tobe SS, Ferrier DEK, Bendena WG, Hui JHL. Micro-RNA Clusters Integrate Evolutionary Constraints on Expression and Target Affinities: The miR-6/5/4/286/3/309 Cluster in Drosophila. Mol Biol Evol 2020; 37:2955-2965. [PMID: 32521021 DOI: 10.1093/molbev/msaa146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
A striking feature of micro-RNAs is that they are often clustered in the genomes of animals. The functional and evolutionary consequences of this clustering remain obscure. Here, we investigated a micro-RNA cluster miR-6/5/4/286/3/309 that is conserved across drosophilid lineages. Small RNA sequencing revealed expression of this micro-RNA cluster in Drosophila melanogaster leg discs, and conditional overexpression of the whole cluster resulted in leg appendage shortening. Transgenic overexpression lines expressing different combinations of micro-RNA cluster members were also constructed. Expression of individual micro-RNAs from the cluster resulted in a normal wild-type phenotype, but either the expression of several ancient micro-RNAs together (miR-5/4/286/3/309) or more recently evolved clustered micro-RNAs (miR-6-1/2/3) can recapitulate the phenotypes generated by the whole-cluster overexpression. Screening of transgenic fly lines revealed downregulation of leg-patterning gene cassettes in generation of the leg-shortening phenotype. Furthermore, cell transfection with different combinations of micro-RNA cluster members revealed a suite of downstream genes targeted by all cluster members, as well as complements of targets that are unique for distinct micro-RNAs. Considered together, the micro-RNA targets and the evolutionary ages of each micro-RNA in the cluster demonstrate the importance of micro-RNA clustering, where new members can reinforce and modify the selection forces on both the cluster regulation and the gene regulatory network of existing micro-RNAs. Key words: micro-RNA, cluster, evolution.
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Affiliation(s)
- Qu Zhe
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
| | - Wing Chung Yiu
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
| | - Ho Yin Yip
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
| | - Wenyan Nong
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
| | - Clare W C Yu
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
| | - Ivy H T Lee
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
| | - Annette Y P Wong
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
| | - Nicola W Y Wong
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
| | - Fiona K M Cheung
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
| | - Ting Fung Chan
- School of Life Sciences, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
| | - Kwok Fai Lau
- School of Life Sciences, The Chinese University of Hong Kong
| | - Silin Zhong
- School of Life Sciences, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
| | - Ka Hou Chu
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, The Chinese University of Hong Kong
| | - Stephen S Tobe
- Department of Cell and Systems Biology, University of Toronto, Canada
| | | | | | - Jerome H L Hui
- School of Life Sciences, Simon F.S. Li Marine Science Laboratory, State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong
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45
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Evaluation of miR-21 Expression Level in Helicobacter pylori-Infected Gastric Mucosa. Jundishapur J Microbiol 2020. [DOI: 10.5812/jjm.100724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background: Gastric cancer is one of the main causes of death worldwide. In this regard, Helicobacter pylori infection is considered as the main risk factor for gastric cancer. MicroRNA (mirNA) can interface with mRNA molecules as well as blocking their translation into proteins or inducing degradation. Objectives: The aim of this study was to compare the expression of mir-21 in biopsy samples of gastritis and healthy adjacent tissues. Methods: Between Feb-Dec 2017, 70 patients with dyspeptic symptoms from Taleghani Hospital were enrolled in this study. Accordingly, the expression level of mir-21 was evaluated using semi-quantitative RT-PCR in mucosal biopsy samples from those well-characterized patients. Moreover, the U6 gene was used as an internal control. Results: Our data indicated that mir-21 expression was significantly up-regulated in the infected samples with H. pylori compared to healthy samples. Conclusions: Our results confirm that H. pylori infection can alter the expression of mir-21 in gastric epithelial cells and gastric mucosal tissues. However, the exact role of the miRNA changes in H. pylori infection will require further experiments.
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46
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Medley JC, Panzade G, Zinovyeva AY. microRNA strand selection: Unwinding the rules. WILEY INTERDISCIPLINARY REVIEWS-RNA 2020; 12:e1627. [PMID: 32954644 PMCID: PMC8047885 DOI: 10.1002/wrna.1627] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 08/18/2020] [Accepted: 08/27/2020] [Indexed: 12/17/2022]
Abstract
microRNAs (miRNAs) play a central role in the regulation of gene expression by targeting specific mRNAs for degradation or translational repression. Each miRNA is post‐transcriptionally processed into a duplex comprising two strands. One of the two miRNA strands is selectively loaded into an Argonaute protein to form the miRNA‐Induced Silencing Complex (miRISC) in a process referred to as miRNA strand selection. The other strand is ejected from the complex and is subject to degradation. The target gene specificity of miRISC is determined by sequence complementarity between the Argonaute‐loaded miRNA strand and target mRNA. Each strand of the miRNA duplex has the capacity to be loaded into miRISC and possesses a unique seed sequence. Therefore, miRNA strand selection plays a defining role in dictating the specificity of miRISC toward its targets and provides a mechanism to alter gene expression in a switch‐like fashion. Aberrant strand selection can lead to altered gene regulation by miRISC and is observed in several human diseases including cancer. Previous and emerging data shape the rules governing miRNA strand selection and shed light on how these rules can be circumvented in various physiological and pathological contexts. This article is categorized under:
RNA Processing > Processing of Small RNAs Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs Regulatory RNAs/RNAi/Riboswitches > Biogenesis of Effector Small RNAs
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Affiliation(s)
- Jeffrey C Medley
- Division of Biology, Kansas State University, Manhattan, Kansas, USA
| | - Ganesh Panzade
- Division of Biology, Kansas State University, Manhattan, Kansas, USA
| | - Anna Y Zinovyeva
- Division of Biology, Kansas State University, Manhattan, Kansas, USA
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47
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Russo GL, Stampone E, Cervellera C, Borriello A. Regulation of p27 Kip1 and p57 Kip2 Functions by Natural Polyphenols. Biomolecules 2020; 10:biom10091316. [PMID: 32933137 PMCID: PMC7564754 DOI: 10.3390/biom10091316] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/01/2020] [Accepted: 09/09/2020] [Indexed: 12/14/2022] Open
Abstract
In numerous instances, the fate of a single cell not only represents its peculiar outcome but also contributes to the overall status of an organism. In turn, the cell division cycle and its control strongly influence cell destiny, playing a critical role in targeting it towards a specific phenotype. Several factors participate in the control of growth, and among them, p27Kip1 and p57Kip2, two proteins modulating various transitions of the cell cycle, appear to play key functions. In this review, the major features of p27 and p57 will be described, focusing, in particular, on their recently identified roles not directly correlated with cell cycle modulation. Then, their possible roles as molecular effectors of polyphenols’ activities will be discussed. Polyphenols represent a large family of natural bioactive molecules that have been demonstrated to exhibit promising protective activities against several human diseases. Their use has also been proposed in association with classical therapies for improving their clinical effects and for diminishing their negative side activities. The importance of p27Kip1 and p57Kip2 in polyphenols’ cellular effects will be discussed with the aim of identifying novel therapeutic strategies for the treatment of important human diseases, such as cancers, characterized by an altered control of growth.
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Affiliation(s)
- Gian Luigi Russo
- National Research Council, Institute of Food Sciences, 83100 Avellino, Italy;
- Correspondence: (G.L.R.); (A.B.); Tel.: +39-0825-299-331 (G.L.R.)
| | - Emanuela Stampone
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 81031 Napoli, Italy;
| | - Carmen Cervellera
- National Research Council, Institute of Food Sciences, 83100 Avellino, Italy;
| | - Adriana Borriello
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 81031 Napoli, Italy;
- Correspondence: (G.L.R.); (A.B.); Tel.: +39-0825-299-331 (G.L.R.)
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Post-transcriptional modulation of cytochrome P450s, Cyp6g1 and Cyp6g2, by miR-310s cluster is associated with DDT-resistant Drosophila melanogaster strain 91-R. Sci Rep 2020; 10:14394. [PMID: 32873850 PMCID: PMC7463240 DOI: 10.1038/s41598-020-71250-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 08/10/2020] [Indexed: 12/15/2022] Open
Abstract
The role of miRNAs in mediating insecticide resistance remains largely unknown, even for the model species Drosophila melanogaster. Building on prior research, this study used microinjection of synthetic miR-310s mimics into DDT-resistant 91-R flies and observed both a significant transcriptional repression of computationally-predicted endogenous target P450 detoxification genes, Cyp6g1 and Cyp6g2, and also a concomitant increase in DDT susceptibility. Additionally, co-transfection of D. melanogaster S2 cells with dual luciferase reporter constructs validated predictions that miR-310s bind to target binding sites in the 3ʹ untranslated regions (3ʹ-UTR) of both Cyp6g1 and Cyp6g2 in vitro. Findings in the current study provide empirical evidence for a link between reduced miRNA expression and an insecticidal resistance phenotype through reduced targeted post-transcriptional suppression of transcripts encoding proteins involved in xenobiotic detoxification. These insights are important for understanding the breadth of adaptive molecular changes that have contributed to the evolution of DDT resistance in D. melanogaster.
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49
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Shah V, Shah J. Recent trends in targeting miRNAs for cancer therapy. J Pharm Pharmacol 2020; 72:1732-1749. [PMID: 32783235 DOI: 10.1111/jphp.13351] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 07/12/2020] [Accepted: 07/15/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVES MicroRNAs (miRNAs) are a type of small noncoding RNA employed by the cells for gene regulation. A single miRNA, typically 22 nucleotides in length, can regulate the expression of numerous genes. Over the past decade, the study of miRNA biology in the context of cancer has led to the development of new diagnostic and therapeutic opportunities. KEY FINDINGS MicroRNA dysregulation is commonly associated with cancer, in part because miRNAs are actively involved in the mechanisms like genomic instabilities, aberrant transcriptional control, altered epigenetic regulation and biogenesis machinery defects. MicroRNAs can regulate oncogenes or tumour suppressor genes and thus when altered can lead to tumorigenesis. Expression profiling of miRNAs has boosted the possibilities of application of miRNAs as potential cancer biomarkers and therapeutic targets, although the feasibility of these approaches will require further validation. SUMMARY In this review, we will focus on how miRNAs regulate tumour development and the potential applications of targeting miRNAs for cancer therapy.
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Affiliation(s)
- Vandit Shah
- Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
| | - Jigna Shah
- Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India
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50
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Min J, Han TS, Sohn Y, Shimizu T, Choi B, Bae SW, Hur K, Kong SH, Suh YS, Lee HJ, Kim JS, Min JK, Kim WH, Kim VN, Choi E, Goldenring JR, Yang HK. microRNA-30a arbitrates intestinal-type early gastric carcinogenesis by directly targeting ITGA2. Gastric Cancer 2020; 23:600-613. [PMID: 32112274 PMCID: PMC7306433 DOI: 10.1007/s10120-020-01052-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Accepted: 02/12/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Spasmolytic polypeptide-expressing metaplasia (SPEM) is considered a precursor lesion of intestinal metaplasia and intestinal-type gastric cancer (GC), but little is known about microRNA alterations during metaplasia and GC developments. Here, we investigate miR-30a expression in gastric lesions and identify its novel target gene which is associated with the intestinal-type GC. METHODS We conducted in situ hybridization and qRT-PCR to determine miR-30a expression in gastric tissues. miR-30a functions were determined through induction or inhibition of miR-30a in GC cell lines. A gene microarray was utilized to confirm miR-30a target genes in GC, and siRNA-mediated target gene suppression and immunostaining were performed. The Cancer Genome Atlas data were utilized to validate gene expressions. RESULTS We found down-regulation of miR-30a during chief cell transdifferentiation into SPEM. MiR-30a level was also reduced in the early stage of GC, and its level was maintained in advanced GC. We identified a novel target gene of miR-30a and ITGA2, and our results showed that either ectopic expression of miR-30a or ITGA2 knockdown suppressed GC cell proliferation, migration, and tumorigenesis. Levels of ITGA2 inversely correlated with levels of miR-30a in human intestinal-type GC. CONCLUSION We found down-regulation of miR-30a in preneoplastic lesions and its tumor-suppressive functions by targeting ITGA2 in GC. The level of ITGA2, which functions as an oncogene, was up-regulated in human GC. The results of this study suggest that coordination of the miR-30a-ITGA2 axis may serve as an important mechanism in the development of gastric precancerous lesions and intestinal-type GC.
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Affiliation(s)
- Jimin Min
- Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul, 03080, South Korea
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, MRB IV 10435F, 2213 Garland Avenue, Nashville, TN, 37232, USA
| | - Tae-Su Han
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
| | - Yoojin Sohn
- Epithelial Biology Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, MRB IV 10435F, 2213 Garland Avenue, Nashville, TN, 37232, USA
- Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Takahiro Shimizu
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, MRB IV 10435F, 2213 Garland Avenue, Nashville, TN, 37232, USA
- Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Boram Choi
- Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul, 03080, South Korea
| | - Seong-Woo Bae
- Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul, 03080, South Korea
| | - Keun Hur
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, South Korea
| | - Seong-Ho Kong
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Yun-Suhk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Hyuk-Joon Lee
- Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul, 03080, South Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Jang-Seong Kim
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
| | - Jeong-Ki Min
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
| | - Woo-Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - V Narry Kim
- School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Eunyoung Choi
- Nashville VA Medical Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Epithelial Biology Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, MRB IV 10435F, 2213 Garland Avenue, Nashville, TN, 37232, USA.
| | - James R Goldenring
- Nashville VA Medical Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Epithelial Biology Center, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, MRB IV 10435F, 2213 Garland Avenue, Nashville, TN, 37232, USA.
- Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
| | - Han-Kwang Yang
- Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-Ro, Jongno-gu, Seoul, 03080, South Korea.
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.
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