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Kuznetsov NV, Statsenko Y, Ljubisavljevic M. An Update on Neuroaging on Earth and in Spaceflight. Int J Mol Sci 2025; 26:1738. [PMID: 40004201 PMCID: PMC11855577 DOI: 10.3390/ijms26041738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 02/06/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
Over 400 articles on the pathophysiology of brain aging, neuroaging, and neurodegeneration were reviewed, with a focus on epigenetic mechanisms and numerous non-coding RNAs. In particular, this review the accent is on microRNAs, the discovery of whose pivotal role in gene regulation was recognized by the 2024 Nobel Prize in Physiology or Medicine. Aging is not a gradual process that can be easily modeled and described. Instead, multiple temporal processes occur during aging, and they can lead to mosaic changes that are not uniform in pace. The rate of change depends on a combination of external and internal factors and can be boosted in accelerated aging. The rate can decrease in decelerated aging due to individual structural and functional reserves created by cognitive, physical training, or pharmacological interventions. Neuroaging can be caused by genetic changes, epigenetic modifications, oxidative stress, inflammation, lifestyle, and environmental factors, which are especially noticeable in space environments where adaptive changes can trigger aging-like processes. Numerous candidate molecular biomarkers specific to neuroaging need to be validated to develop diagnostics and countermeasures.
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Affiliation(s)
- Nik V. Kuznetsov
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (M.L.)
| | - Yauhen Statsenko
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (M.L.)
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Milos Ljubisavljevic
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (M.L.)
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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Barancheshmeh M, Najafzadehvarzi H, Shokrzadeh N, Aram C. Comparative analysis of fennel essential oil and manganese in PCOS rat model via modulating miR-145 expression and structure-based virtual screening of IGF2R protein to address insulin resistance and obesity. OBESITY MEDICINE 2025; 53:100574. [DOI: 10.1016/j.obmed.2024.100574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Song G, Yu X, Shi H, Sun B, Amateau S. miRNAs in HCC, pathogenesis, and targets. Hepatology 2024:01515467-990000000-01097. [PMID: 39626210 DOI: 10.1097/hep.0000000000001177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 11/22/2024] [Indexed: 12/21/2024]
Abstract
Liver cancer is the third leading cause of cancer-related mortality worldwide. HCC, the most common type of primary liver cancer, is driven by complex genetic, epigenetic, and environmental factors. MicroRNAs, a class of naturally occurring small noncoding RNAs, play crucial roles in HCC by simultaneously modulating the expression of multiple genes in a fine-tuning manner. Significant progress has been made in understanding how miRNAs influence key oncogenic pathways, including cell proliferation, apoptosis, angiogenesis, and epithelial-mesenchymal transition (EMT), as well as their role in modulating the immune microenvironment in HCC. Due to the unexpected stability of miRNAs in the blood and fixed HCC tumors, recent advancements also highlight their potential as noninvasive diagnostic tools. Restoring or inhibiting specific miRNAs has offered promising strategies for targeted HCC treatment by suppressing malignant hepatocyte growth and enhancing antitumor immunity. In this comprehensive review, we consolidate previous research and provide the latest insights into how miRNAs regulate HCC and their therapeutic and diagnostic potential. We delve into the dysregulation of miRNA biogenesis in HCC, the roles of miRNAs in the proliferation and apoptosis of malignant hepatocytes, angiogenesis and metastasis of HCC, the immune microenvironment in HCC, and drug resistance. We also discuss the therapeutic and diagnostic potential of miRNAs and delivery approaches of miRNA drugs to overcome the limitations of current HCC treatment options. By thoroughly summarizing the roles of miRNAs in HCC, our goal is to advance the development of effective therapeutic drugs with minimal adverse effects and to establish precise tools for early diagnosis of HCC.
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Affiliation(s)
- Guisheng Song
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Xiaofan Yu
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Hongtao Shi
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
- Department of Cardiology, the First Hospital of Shanxi Medical University, Taiyuan City, China
| | - Bo Sun
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Stuart Amateau
- Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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Statsenko Y, Kuznetsov NV, Morozova D, Liaonchyk K, Simiyu GL, Smetanina D, Kashapov A, Meribout S, Gorkom KNV, Hamoudi R, Ismail F, Ansari SA, Emerald BS, Ljubisavljevic M. Reappraisal of the Concept of Accelerated Aging in Neurodegeneration and Beyond. Cells 2023; 12:2451. [PMID: 37887295 PMCID: PMC10605227 DOI: 10.3390/cells12202451] [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: 08/04/2023] [Revised: 09/01/2023] [Accepted: 09/06/2023] [Indexed: 10/28/2023] Open
Abstract
BACKGROUND Genetic and epigenetic changes, oxidative stress and inflammation influence the rate of aging, which diseases, lifestyle and environmental factors can further accelerate. In accelerated aging (AA), the biological age exceeds the chronological age. OBJECTIVE The objective of this study is to reappraise the AA concept critically, considering its weaknesses and limitations. METHODS We reviewed more than 300 recent articles dealing with the physiology of brain aging and neurodegeneration pathophysiology. RESULTS (1) Application of the AA concept to individual organs outside the brain is challenging as organs of different systems age at different rates. (2) There is a need to consider the deceleration of aging due to the potential use of the individual structure-functional reserves. The latter can be restored by pharmacological and/or cognitive therapy, environment, etc. (3) The AA concept lacks both standardised terminology and methodology. (4) Changes in specific molecular biomarkers (MBM) reflect aging-related processes; however, numerous MBM candidates should be validated to consolidate the AA theory. (5) The exact nature of many potential causal factors, biological outcomes and interactions between the former and the latter remain largely unclear. CONCLUSIONS Although AA is commonly recognised as a perspective theory, it still suffers from a number of gaps and limitations that assume the necessity for an updated AA concept.
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Affiliation(s)
- Yauhen Statsenko
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Big Data Analytic Center, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Nik V. Kuznetsov
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
| | - Daria Morozova
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
| | - Katsiaryna Liaonchyk
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
| | - Gillian Lylian Simiyu
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Darya Smetanina
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Aidar Kashapov
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Sarah Meribout
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Klaus Neidl-Van Gorkom
- Department of Radiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates; (Y.S.); (G.L.S.); (D.S.); (A.K.); (S.M.); (K.N.-V.G.)
| | - Rifat Hamoudi
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
- Division of Surgery and Interventional Science, University College London, London NW3 2PS, UK
| | - Fatima Ismail
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
| | - Suraiya Anjum Ansari
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Biochemistry and Molecular Biology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Bright Starling Emerald
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Milos Ljubisavljevic
- ASPIRE Precision Medicine Research Institute Abu Dhabi, United Arab Emirates University, Al Ain 27272, United Arab Emirates; (D.M.); (K.L.); (R.H.); (S.A.A.); (B.S.E.); (M.L.)
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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Lucarini V, Nardozi D, Angiolini V, Benvenuto M, Focaccetti C, Carrano R, Besharat ZM, Bei R, Masuelli L. Tumor Microenvironment Remodeling in Gastrointestinal Cancer: Role of miRNAs as Biomarkers of Tumor Invasion. Biomedicines 2023; 11:1761. [PMID: 37371856 DOI: 10.3390/biomedicines11061761] [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: 05/10/2023] [Revised: 06/13/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
Gastrointestinal (GI) cancers are the most frequent neoplasm, responsible for half of all cancer-related deaths. Metastasis is the leading cause of death from GI cancer; thus, studying the processes that regulate cancer cell migration is of paramount importance for the development of new therapeutic strategies. In this review, we summarize the mechanisms adopted by cancer cells to promote cell migration and the subsequent metastasis formation by highlighting the key role that tumor microenvironment components play in deregulating cellular pathways involved in these processes. We, therefore, provide an overview of the role of different microRNAs in promoting tumor metastasis and their role as potential biomarkers for the prognosis, monitoring, and diagnosis of GI cancer patients. Finally, we relate the possible use of nutraceuticals as a new strategy for targeting numerous microRNAs and different pathways involved in GI tumor invasiveness.
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Affiliation(s)
- Valeria Lucarini
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
| | - Daniela Nardozi
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Valentina Angiolini
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
| | - Monica Benvenuto
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
- Departmental Faculty of Medicine and Surgery, Saint Camillus International University of Health and Medical Sciences, via di Sant'Alessandro 8, 00131 Rome, Italy
| | - Chiara Focaccetti
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Raffaele Carrano
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Zein Mersini Besharat
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
| | - Roberto Bei
- Department of Clinical Sciences and Translational Medicine, University of Rome "Tor Vergata", Via Montpellier 1, 00133 Rome, Italy
| | - Laura Masuelli
- Department of Experimental Medicine, University of Rome "Sapienza", Viale Regina Elena 324, 00161 Rome, Italy
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Shen X, Tang J, Jiang R, Wang X, Yang Z, Huang Y, Lan X, Lei C, Chen H. CircRILPL1 promotes muscle proliferation and differentiation via binding miR-145 to activate IGF1R/PI3K/AKT pathway. Cell Death Dis 2021; 12:142. [PMID: 33542215 PMCID: PMC7862392 DOI: 10.1038/s41419-021-03419-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 12/11/2020] [Accepted: 12/17/2020] [Indexed: 12/22/2022]
Abstract
Many novel non-coding RNAs, such as microRNAs (miRNAs) and circular RNAs (circRNAs), are involved in various physiological and pathological processes. The PI3K/AKT signaling pathway is important for its role in regulating skeletal muscle development. In this study, molecular and biochemical assays were used to confirm the role of miRNA-145 (miR-145) in myoblast proliferation and apoptosis. Based on sequencing data and bioinformatics analysis, we identified a new circRILPL1, which acts as a sponge for miR-145. The interactions between circRILPL1 and miR-145 were examined by bioinformatics, a luciferase assay, and RNA immunoprecipitation. Mechanistically, knockdown or exogenous expression of circRILPL1 in the primary myoblasts was performed to prove the functional significance of circRILPL1. We investigated the inhibitory effect of miR-145 on myoblast proliferation by targeting IGF1R to regulate the PI3K/AKT signaling pathway. A novel circRILPL1 was identified that could sponge miR-145 and is related to AKT activation. In addition, circRILPL1 was positively correlated with muscle proliferation and differentiation in vitro and could inhibit cell apoptosis. The newly identified circRILPL1 functions as a miR-145 sponge to regulate the IGF1R gene and rescue the inhibitory effect of miR-145 on the PI3K/AKT signaling pathway, thereby promoting myoblast growth.
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Affiliation(s)
- Xuemei Shen
- Key laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Jia Tang
- Key laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Rui Jiang
- Key laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Xiaogang Wang
- Key laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Zhaoxin Yang
- Key laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Yongzhen Huang
- Key laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Xianyong Lan
- Key laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Chuzhao Lei
- Key laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Hong Chen
- Key laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
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Morishita A, Oura K, Tadokoro T, Fujita K, Tani J, Masaki T. MicroRNAs in the Pathogenesis of Hepatocellular Carcinoma: A Review. Cancers (Basel) 2021; 13:cancers13030514. [PMID: 33572780 PMCID: PMC7866004 DOI: 10.3390/cancers13030514] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers, and the prognosis for late-stage HCC remains poor. A better understanding of the pathogenesis of HCC is expected to improve outcomes. MicroRNAs (miRNAs) are small, noncoding, single-stranded RNAs that regulate the expression of various target genes, including those in cancer-associated genomic regions or fragile sites in various human cancers. We summarize the central roles of miRNAs in the pathogenesis of HCC and discuss their potential utility as valuable biomarkers and new therapeutic agents for HCC. Abstract Hepatocellular carcinoma (HCC) is the seventh most frequent cancer and the fourth leading cause of cancer mortality worldwide. Despite substantial advances in therapeutic strategies, the prognosis of late-stage HCC remains dismal because of the high recurrence rate. A better understanding of the etiology of HCC is therefore necessary to improve outcomes. MicroRNAs (miRNAs) are small, endogenous, noncoding, single-stranded RNAs that modulate the expression of their target genes at the posttranscriptional and translational levels. Aberrant expression of miRNAs has frequently been detected in cancer-associated genomic regions or fragile sites in various human cancers and has been observed in both HCC cells and tissues. The precise patterns of aberrant miRNA expression differ depending on disease etiology, including various causes of hepatocarcinogenesis, such as viral hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis. However, little is known about the underlying mechanisms and the association of miRNAs with the pathogenesis of HCC of various etiologies. In the present review, we summarize the key mechanisms of miRNAs in the pathogenesis of HCC and emphasize their potential utility as valuable diagnostic and prognostic biomarkers, as well as innovative therapeutic targets, in HCC diagnosis and treatment.
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Pan S, Zhao X, Shao C, Fu B, Huang Y, Zhang N, Dou X, Zhang Z, Qiu Y, Wang R, Jin M, Kong D. STIM1 promotes angiogenesis by reducing exosomal miR-145 in breast cancer MDA-MB-231 cells. Cell Death Dis 2021; 12:38. [PMID: 33414420 PMCID: PMC7791041 DOI: 10.1038/s41419-020-03304-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 11/25/2020] [Accepted: 11/27/2020] [Indexed: 12/16/2022]
Abstract
Cancer cells secrete abundant exosomes, and the secretion can be promoted by an increase of intracellular Ca2+. Stromal interaction molecule 1 (STIM1) plays a key role in shaping Ca2+ signals. MicroRNAs (miRNAs) have been reported to be potential therapeutic targets for many diseases, including breast cancer. Recently, we investigated the effect of exosomes from STIM1-knockout breast cancer MDA-MB-231 cells (Exo-STIM1-KO), and from SKF96365-treated MDA-MB-231 cells (Exo-SKF) on angiogenesis in human umbilical vein endothelial cells (HUVECs) and nude mice. The exosomes Exo-STIM1-KO and Exo-SKF inhibited tube formation by HUVECs remarkably. The miR-145 was increased in SKF96365 treated or STIM1-knockout MDA-MB-231 cells, Exo-SKF and Exo-STIM1-KO, and HUVECs treated with Exo-SKF or Exo-STIM1-KO. Moreover, the expressions of insulin receptor substrate 1 (IRS1), which is the target of miR-145, and the downstream proteins such as Akt/mammalian target of rapamycin (mTOR), Raf/extracellular signal regulated-protein kinase (ERK), and p38 were markedly inhibited in HUVECs treated with Exo-SKF or Exo-STIM1-KO. Matrigel plug assay in vivo showed that tumor angiogenesis was suppressed in Exo-STIM1-KO, but promoted when miR-145 antagomir was added. Taken together, our findings suggest that STIM1 promotes angiogenesis by reducing exosomal miR-145 in breast cancer MDA-MB-231 cells.
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Affiliation(s)
- Shunli Pan
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Xiaoxia Zhao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Chen Shao
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Bingjie Fu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Yingying Huang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Ning Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Xiaojing Dou
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Zhe Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Yuling Qiu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Ran Wang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China
| | - Meihua Jin
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China.
| | - Dexin Kong
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, 300070, Tianjin, China.
- School of Medicine, Tianjin Tianshi College, Tianyuan University, 301700, Tianjin, China.
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Lan S, Albinsson S. Regulation of IRS-1, insulin signaling and glucose uptake by miR-143/145 in vascular smooth muscle cells. Biochem Biophys Res Commun 2020; 529:119-125. [PMID: 32560812 DOI: 10.1016/j.bbrc.2020.05.148] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 05/20/2020] [Indexed: 11/25/2022]
Abstract
Regulation of insulin signaling by microRNAs in smooth muscle cells may contribute to diabetic vascular disease. The two smooth muscle enriched miRNAs miR-143 and miR-145 have been reported to target mediators of insulin signaling in non-smooth muscle cells. In this study, we aimed to determine the importance of this regulation in vascular smooth muscle cells, where expression of miR-143/145 is much higher than in other cell types. Smooth muscle cells deficient of the miR-143/145 cluster were used, as well as smooth muscle cells transfected with mimics/inhibitors for either miR-143 or miR-145. We found that deletion of miR-143/145 in smooth muscle results in a dramatic upregulation IRS-1 expression and insulin signaling, and an increased insulin-induced glucose uptake. Furthermore, specific modulation of either miR-145 or miR-143 expression regulated specific targets (IRS-1, ORP8 and the IGF-1 receptor) in the insulin signaling pathway. Consequently, transient inhibition or overexpression of either miR-143 or miR-145 was sufficient to regulate insulin signaling in smooth muscle cells. In conclusion, the results of this study support an important role for both miR-143 and miR-145 in the regulation of insulin signaling and glucose uptake in vascular smooth muscle cells.
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MESH Headings
- Animals
- Biological Transport, Active
- Cells, Cultured
- Glucose/metabolism
- Insulin/metabolism
- Insulin Receptor Substrate Proteins/metabolism
- Mice
- Mice, Knockout
- MicroRNAs/antagonists & inhibitors
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/metabolism
- Myocytes, Smooth Muscle/cytology
- Myocytes, Smooth Muscle/metabolism
- Receptor, IGF Type 1/metabolism
- Signal Transduction
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Affiliation(s)
- Susan Lan
- Department of Experimental Medical Science, Lund University, Lund, Sweden
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10
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Yamashita H, Surapureddi S, Kovi RC, Bhusari S, Ton TV, Li JL, Shockley KR, Peddada SD, Gerrish KE, Rider CV, Hoenerhoff MJ, Sills RC, Pandiri AR. Unique microRNA alterations in hepatocellular carcinomas arising either spontaneously or due to chronic exposure to Ginkgo biloba extract (GBE) in B6C3F1/N mice. Arch Toxicol 2020; 94:2523-2541. [PMID: 32306082 DOI: 10.1007/s00204-020-02749-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 04/08/2020] [Indexed: 12/18/2022]
Abstract
Ginkgo biloba extract (GBE) is used in traditional Chinese medicine as a herbal supplement for improving memory. Exposure of B6C3F1/N mice to GBE in a 2-year National Toxicology Program (NTP) bioassay resulted in a dose-dependent increase in hepatocellular carcinomas (HCC). To identify key microRNAs that modulate GBE-induced hepatocarcinogenesis, we compared the global miRNA expression profiles in GBE-exposed HCC (GBE-HCC) and spontaneous HCC (SPNT-HCC) with age-matched vehicle control normal livers (CNTL) from B6C3F1/N mice. The number of differentially altered miRNAs in GBE-HCC and SPNT-HCC was 74 (52 up and 22 down) and 33 (15 up and 18 down), respectively. Among the uniquely differentially altered miRNAs in GBE-HCC, miR-31 and one of its predicted targets, Cdk1 were selected for functional validation. A potential miRNA response element (MRE) in the 3'-untranslated regions (3'-UTR) of Cdk1 mRNA was revealed by in silico analysis and confirmed by luciferase assays. In mouse hepatoma cell line HEPA-1 cells, we demonstrated an inverse correlation between miR-31 and CDK1 protein levels, but no change in Cdk1 mRNA levels, suggesting a post-transcriptional effect. Additionally, a set of miRNAs (miRs-411, 300, 127, 134, 409-3p, and 433-3p) that were altered in the GBE-HCCs were also altered in non-tumor liver samples from the 90-day GBE-exposed group compared to the vehicle control group, suggesting that some of these miRNAs could serve as potential biomarkers for GBE exposure or hepatocellular carcinogenesis. These data increase our understanding of miRNA-mediated epigenetic regulation of GBE-mediated hepatocellular carcinogenesis in B6C3F1/N mice.
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MESH Headings
- 3' Untranslated Regions
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- CDC2 Protein Kinase/genetics
- CDC2 Protein Kinase/metabolism
- Carcinoma, Hepatocellular/chemically induced
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Cell Line, Tumor
- Cell Transformation, Neoplastic/chemically induced
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Epigenesis, Genetic
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Ginkgo biloba
- Liver Neoplasms/chemically induced
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Male
- Mice
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Plant Extracts/toxicity
- Time Factors
- Transcriptome
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Affiliation(s)
- Haruhiro Yamashita
- Cellular and Molecular Pathology Branch, DNTP, NIEHS, Research Triangle Park, NC, 27709, USA
- Frontier Research Center, Taisho Pharmaceutical Co. Ltd, Tokyo, 100-6609, Japan
| | - Sailesh Surapureddi
- Signal Transduction Laboratory, DIR, NIEHS, Research Triangle Park, NC, 27709, USA
- United States Environmental Protection Agency, 1200 Pennsylvania Avenue NW, Washington, DC, 20460, USA
| | - Ramesh C Kovi
- Cellular and Molecular Pathology Branch, DNTP, NIEHS, Research Triangle Park, NC, 27709, USA
- Experimental Pathology Laboratories Inc, Research Triangle Park, NC, 27709, USA
| | - Sachin Bhusari
- Cellular and Molecular Pathology Branch, DNTP, NIEHS, Research Triangle Park, NC, 27709, USA
- Global Scientific and Regulatory Affairs, The Coca-Cola Company, 1 Coca Cola Plaza, NW, Atlanta, GA, USA
| | - Thai Vu Ton
- Cellular and Molecular Pathology Branch, DNTP, NIEHS, Research Triangle Park, NC, 27709, USA
| | - Jian-Liang Li
- Integrative Bioinformatics Support Group, DIR, NIEHS, Research Triangle Park, NC, 27709, USA
| | - Keith R Shockley
- Biostatistics and Computational Biology Branch, DIR, NIEHS, Research Triangle Park, NC, 27709, USA
| | - Shyamal D Peddada
- Biostatistics and Computational Biology Branch, DIR, NIEHS, Research Triangle Park, NC, 27709, USA
- Department of Biostatistics, University of Pittsburgh, 7126 Public Health, 130 DeSoto Street, Pittsburgh, PA, 1526, USA
| | - Kevin E Gerrish
- Molecular Genomics Core Laboratory, DIR, NIEHS, Research Triangle Park, NC, 27709, USA
| | - Cynthia V Rider
- Toxicology Branch, DNTP, NIEHS, Research Triangle Park, NC, 27709, USA
| | - Mark J Hoenerhoff
- Cellular and Molecular Pathology Branch, DNTP, NIEHS, Research Triangle Park, NC, 27709, USA
- In Vivo Animal Core, Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Robert C Sills
- Cellular and Molecular Pathology Branch, DNTP, NIEHS, Research Triangle Park, NC, 27709, USA
| | - Arun R Pandiri
- Cellular and Molecular Pathology Branch, DNTP, NIEHS, Research Triangle Park, NC, 27709, USA.
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11
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Aly DM, Gohar NAH, Abd El-Hady AA, Khairy M, Abdullatif MM. Serum microRNA let-7a-1/let-7d/let-7f and miRNA 143/145 Gene Expression Profiles as Potential Biomarkers in HCV Induced Hepatocellular Carcinoma. Asian Pac J Cancer Prev 2020; 21:555-562. [PMID: 32102538 PMCID: PMC7332122 DOI: 10.31557/apjcp.2020.21.2.555] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Indexed: 12/27/2022] Open
Abstract
Background: Egypt has the highest prevalence of hepatitis C virus (HCV) worldwide. Which make liver cirrhosis and hepatocellular carcinoma (HCC) major health concerns in Egypt. Circulating microRNAs (miRNAs) have been investigated as biomarkers for malignancies. We investigated miRNA gene expression of Lethal-7 (let-7) cluster: let7-a-1, let-7d-1, let-7f-1 and miRNA (miR)143/145 cluster in sera of HCC patients and chronic HCV patients. Methods: The study included 40 post HCV-Hepatocellular carcinoma patients, 40 chronic HCV patients divided into 2 subgroups, 20 cirrhotic patients and 20 non-cirrhotic patients, and 40 apparently healthy subjects as a control group. Gene expression analysis for studied miRNAs was done using quantitative SYBR Green reverse-transcription Real-Time polymerase chain reaction (PCR). Results: We found that Let-7a-1 gene expression was significantly downregulated in the serum of HCV-HCC patients than in HCV non HCC cirrhotic group and was significantly upregulated in the serum of liver cirrhosis patients than HCV non-cirrhotic group. miR-143 and miR-145 expressions were significantly downregulated in the serum of HCC patients than in control group and miR-143 was significantly downregulated in the serum of non-cirrhotic HCV patients than in control group. Conclusion: The downregulation of serum let-7-a1, miR-143, and miR-145 gene expression may exhibit significant influence on the development of HCC in chronic HCV Egyptian patients and can be used as biomarkers for HCC diagnosis.
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Affiliation(s)
- Doaa Mamdouh Aly
- Clinical and Chemical Pathology Department, Theodor Bilharz Research Institute, Egypt
| | | | | | - Marwa Khairy
- Endemic Medicine and Hepatology Unit, Faculty of Medicine, Cairo University, Egypt
| | - Mona Mohsen Abdullatif
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Egypt
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12
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MicroRNAs in Animal Models of HCC. Cancers (Basel) 2019; 11:cancers11121906. [PMID: 31805631 PMCID: PMC6966618 DOI: 10.3390/cancers11121906] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/27/2019] [Accepted: 11/28/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.
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13
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Nasr MA, Salah RA, Abd Elkodous M, Elshenawy SE, El-Badri N. Dysregulated MicroRNA Fingerprints and Methylation Patterns in Hepatocellular Carcinoma, Cancer Stem Cells, and Mesenchymal Stem Cells. Front Cell Dev Biol 2019; 7:229. [PMID: 31681762 PMCID: PMC6811506 DOI: 10.3389/fcell.2019.00229] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 09/26/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the top causes of cancer mortality worldwide. Although HCC has been researched extensively, there is still a need for novel and effective therapeutic interventions. There is substantial evidence that initiation of carcinogenesis in liver cirrhosis, a leading cause of HCC, is mediated by cancer stem cells (CSCs). CSCs were also shown to be responsible for relapse and chemoresistance in several cancers, including HCC. MicroRNAs (miRNAs) constitute important epigenetic markers that regulate carcinogenesis by acting post-transcriptionally on mRNAs, contributing to the progression of HCC. We have previously shown that co-culture of cancer cells with mesenchymal stem cells (MSCs) could induce the reprogramming of MSCs into CSC-like cells. In this review, we evaluate the available data concerning the epigenetic regulation of miRNAs through methylation and the possible role of this regulation in stem cell and somatic reprogramming in HCC.
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Affiliation(s)
- Mohamed A Nasr
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Radwa Ayman Salah
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - M Abd Elkodous
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Shimaa E Elshenawy
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
| | - Nagwa El-Badri
- Center of Excellence for Stem Cells and Regenerative Medicine (CESC), Zewail City of Science and Technology, 6th of October City, Egypt
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14
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Qi Z, Li S, Su Y, Zhang J, Kang Y, Huang Y, Jin F, Xing Q. Role of microRNA-145 in protection against myocardial ischemia/reperfusion injury in mice by regulating expression of GZMK with the treatment of sevoflurane. J Cell Physiol 2019; 234:16526-16539. [PMID: 30873621 DOI: 10.1002/jcp.28323] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 01/23/2019] [Accepted: 01/24/2019] [Indexed: 01/24/2023]
Abstract
This study aims to investigate the role of microRNA-145 (miR-145) in protection against myocardial ischemia/reperfusion (I/R) injury in mice by regulating expression of granzyme K (GZMK) with the treatment of sevoflurane. The mice model of myocardial I/R injury was established by left coronary artery ligation. The expression of miR-145 and GZMK in myocardial tissues of mice was detected by Reverse transcription quantitative polymerase chain reaction and western blot analysis. The changes of the cardiac function and hemodynamics, pathological changes of myocardial tissues, the ultrastructure of cardiomyocytes, myocardial infarction area, and cardiomyocyte apoptosis were observed. The expression of the apoptosis-related protein cleaved-caspase-3, Bax, and Bcl-2 was detected by western blot analysis. The levels of malondialdehyde, myeloperoxidase, superoxide dismutase in myocardial tissues were detected by spectrophotometric colorimetry. The levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α in the serum of mice were detected by the enzyme-linked immunosorbent assay. The level of oxidative stress and the expression of inflammatory factors increased in mice with myocardial I/R injury. Sevoflurane postconditioning could reduce myocardial I/R injury in mice. Sevoflurane postconditioning may protect myocardial I/R injury through miR-145-regulation of GZMK in mice. Inhibition of miR-145 expression could reduce the protective effect of sevoflurane posttreatment on myocardial I/R injury in mice. Low expression of GZMK could attenuate the inhibitory effect of miR-145 on myocardial I/R injury after sevoflurane treatment in mice. Our study suggests that sevoflurane postconditioning may protect against myocardial I/R injury by upregulating miR-145 expression and downregulating GZMK expression.
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Affiliation(s)
- Zheng Qi
- Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Shushan Li
- Department of Orthopedics, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, People's Republic of China
| | - Yu Su
- Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
| | - Ji Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Yu Kang
- Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, People's Republic of China
| | - Yunli Huang
- Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Feng Jin
- Department of Anesthesiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
| | - Qinghe Xing
- Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
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15
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Chaturvedi VK, Singh A, Dubey SK, Hetta HF, John J, Singh M. Molecular mechanistic insight of hepatitis B virus mediated hepatocellular carcinoma. Microb Pathog 2019; 128:184-194. [PMID: 30611768 DOI: 10.1016/j.micpath.2019.01.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 12/30/2018] [Accepted: 01/02/2019] [Indexed: 02/07/2023]
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16
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Xu L, Zhang Y, Tang J, Wang P, Li L, Yan X, Zheng X, Ren S, Zhang M, Xu M. The Prognostic Value and Regulatory Mechanisms of microRNA-145 in Various Tumors: A Systematic Review and Meta-analysis of 50 Studies. Cancer Epidemiol Biomarkers Prev 2019; 28:867-881. [PMID: 30602498 DOI: 10.1158/1055-9965.epi-18-0570] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 08/16/2018] [Accepted: 12/26/2018] [Indexed: 02/05/2023] Open
Abstract
Acting as an important tumor-related miRNA, the clinical significance and underlying mechanisms of miR-145 in various malignant tumors have been investigated by numerous studies. This study aimed to comprehensively estimate the prognostic value and systematically illustrate the regulatory mechanisms of miR-145 based on all eligible literature.Relevant studies were acquired from multiple online databases. Overall survival (OS) and progression-free survival (PFS) were used as primary endpoints. Detailed subgroup analyses were performed to decrease the heterogeneity among studies and recognize the prognostic value of miR-145. All statistical analyses were performed with RevMan software version 5.3 and STATA software version 14.1. A total of 48 articles containing 50 studies were included in the meta-analysis. For OS, the pooled results showed that low miR-145 expression in tumor tissues was significantly associated with worse OS in patients with various tumors [HR = 1.70; 95% confidence interval (CI), 1.46-1.99; P < 0.001). Subgroup analysis based on tumor type showed that the downregulation of miR-145 was associated with unfavorable OS in colorectal cancer (HR = 2.17; 95% CI, 1.52-3.08; P < 0.001), ovarian cancer (HR = 2.15; 95% CI, 1.29-3.59; P = 0.003), gastric cancer (HR = 1.78; 95% CI, 1.35-2.36; P < 0.001), glioma (HR = 1.65; 95% CI, 1.30-2.10; P < 0.001), and osteosarcoma (HR = 2.28; 95% CI, 1.50-3.47; P < 0.001). For PFS, the pooled results also showed that the downregulation of miR-145 was significantly associated with poor PFS in patients with multiple tumors (HR = 1.39; 95% CI, 1.16-1.67; P < 0.001), and the subgroup analyses further identified that the low miR-145 expression was associated with worse PFS in patients with lung cancer (HR = 1.97; 95% CI, 1.25-3.09; P = 0.003) and those of Asian descent (HR = 1.50; 95% CI, 1.23-1.82; P < 0.001). For the regulatory mechanisms, we observed that numerous tumor-related transcripts could be targeted by miR-145-5p or miR-145-3p, as well as the expression and function of miR-145-5p could be regulated by multiple molecules.This meta-analysis indicated that downregulated miR-145 in tumor tissues or peripheral blood predicted unfavorable prognostic outcomes for patients suffering from various malignant tumors. In addition, miR-145 was involved in multiple tumor-related pathways and the functioning of significant biological effects. miR-145 is a well-demonstrated tumor suppressor, and its expression level is significantly correlated with the prognosis of patients with multiple malignant tumors.
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Affiliation(s)
- Liangliang Xu
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yanfang Zhang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jianwei Tang
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Peng Wang
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Lian Li
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiaokai Yan
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiaobo Zheng
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Shengsheng Ren
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Ming Zhang
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingqing Xu
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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17
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Singh AK, Kumar R, Pandey AK. Hepatocellular Carcinoma: Causes, Mechanism of Progression and Biomarkers. Curr Chem Genom Transl Med 2018; 12:9-26. [PMID: 30069430 PMCID: PMC6047212 DOI: 10.2174/2213988501812010009] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 05/15/2018] [Accepted: 05/20/2018] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular Carcinoma (HCC) is one of the most common malignant tumours in the world. It is a heterogeneous group of a tumour that vary in risk factor and genetic and epigenetic alteration event. Mortality due to HCC in last fifteen years has increased. Multiple factors including viruses, chemicals, and inborn and acquired metabolic diseases are responsible for its development. HCC is closely associated with hepatitis B virus, and at least in some regions of the world with hepatitis C virus. Liver injury caused by viral factor affects many cellular processes such as cell signalling, apoptosis, transcription, DNA repair which in turn induce important effects on cell survival, growth, transformation and maintenance. Molecular mechanisms of hepatocellular carcinogenesis may vary depending on different factors and this is probably why a large set of mechanisms have been associated with these tumours. Various biomarkers including α-fetoprotein, des-γ-carboxyprothrombin, glypican-3, golgi protein-73, squamous cell carcinoma antigen, circulating miRNAs and altered DNA methylation pattern have shown diagnostic significance. This review article covers up key molecular pathway alterations, biomarkers for diagnosis of HCC, anti-HCC drugs and relevance of key molecule/pathway/receptor as a drug target.
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Affiliation(s)
| | | | - Abhay K. Pandey
- Department of Biochemistry, University of Allahabad, Allahabad 211002, India
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18
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Chen E, Xu X, Liu R, Liu T. Small but Heavy Role: MicroRNAs in Hepatocellular Carcinoma Progression. BIOMED RESEARCH INTERNATIONAL 2018; 2018:6784607. [PMID: 29951542 PMCID: PMC5987324 DOI: 10.1155/2018/6784607] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 02/08/2018] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC), which accounts for 85-90% of primary liver cancer, is the fifth most common malignant tumor and the third leading cause of cancer-related deaths worldwide, but the pathological mechanism of HCC is still not fully elucidated. miRNAs are evolutionarily endogenous small noncoding RNAs that negatively regulate gene expression via posttranscriptional inhibition or target mRNA degradation in several diseases, especially human cancer. Therefore, discovering the roles of miRNAs is appealing to scientific researchers. Emerging evidence has shown that the aberrant expressions of numerous miRNAs are involved in many HCC biological processes. In hepatocarcinogenesis, miRNAs with dysregulated expression can exert their function as oncogenes or tumor suppressors depending on their cellular target during the cell cycle, and in tumor development, differentiation, apoptosis, angiogenesis, metastasis, and progression of the tumor microenvironment. In this review, we summarize current findings on miRNAs and assess their functions to explore the molecular mechanisms of tumor progression in HCC.
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Affiliation(s)
- Erbao Chen
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaojing Xu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ruiqi Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
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19
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Cheng H, Xue J, Yang S, Chen Y, Wang Y, Zhu Y, Wang X, Kuang D, Ruan Q, Duan Y, Wang G. Co-targeting of IGF1R/mTOR pathway by miR-497 and miR-99a impairs hepatocellular carcinoma development. Oncotarget 2018. [PMID: 28624790 PMCID: PMC5564620 DOI: 10.18632/oncotarget.18207] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Persistent activation of IGF1R/mTOR signaling pathway plays crucial role in the development of hepatocellular carcinoma (HCC). Therefore, our goal was to elucidate microRNAs (miRNAs) targeting IGF1R/mTOR and the therapeutic potential of single or dual miRNA on HCC development. In this study, we found that miR-497 and miR-99a that target the 3′-UTR of both IGF1R and mTOR were down-regulated in HCC human tissues and cell lines. Functional assay revealed that ectopic expression of miR-497 or miR-99a in HCC cells resulted in a significant inhibition on tumor growth and invasiveness in vitro and tumor development in vivo via repressing the expression of IGF1R and mTOR. Such inhibitory effect on tumor growth is reversed by application of IGF1 ((IGF1R ligand) or MHY1485 (mTOR agonist) in vitro. Furthermore, we found that simultaneous over-expression of both miR-497 and miR-99a exhibited much stronger inhibitory effects on tumor growth than their individual effect, which is still correlated with significantly stronger repression of IGF1R and mTOR. Overall, our results suggest that miR-497 and miR-99a both function as tumor-suppressive miRNAs by suppressing IGF1R/mTOR signaling pathway. The synergistic actions of these two miRNAs partly correlated with IGF1R and mTOR levels, which may represent new strategies for the molecular treatment of HCC.
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Affiliation(s)
- Henghui Cheng
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Jin Xue
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Shouhua Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Yaobin Chen
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Yu Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Yuanli Zhu
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Xiaoyan Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Dong Kuang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Qiurong Ruan
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Yaqi Duan
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
| | - Guoping Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China.,Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P. R. China
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20
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Erstad DJ, Fuchs BC, Tanabe KK. Molecular signatures in hepatocellular carcinoma: A step toward rationally designed cancer therapy. Cancer 2018; 124:3084-3104. [DOI: 10.1002/cncr.31257] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Revised: 12/12/2017] [Accepted: 12/13/2017] [Indexed: 12/14/2022]
Affiliation(s)
- Derek J. Erstad
- Department of SurgeryMassachusetts General HospitalBoston Massachusetts
| | - Bryan C. Fuchs
- Division of Surgical OncologyMassachusetts General HospitalBoston Massachusetts
| | - Kenneth K. Tanabe
- Division of Surgical OncologyMassachusetts General HospitalBoston Massachusetts
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21
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Sathyanarayanan A, Chandrasekaran KS, Karunagaran D. microRNA-145 downregulates SIP1-expression but differentially regulates proliferation, migration, invasion and Wnt signaling in SW480 and SW620 cells. J Cell Biochem 2018; 119:2022-2035. [PMID: 28833449 DOI: 10.1002/jcb.26365] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 08/16/2017] [Indexed: 01/03/2025]
Abstract
microRNA-145 (miR-145) has been shown to act as a tumor suppressor in colorectal cancer but its role in the regulation of epithelial-mesenchymal transition (EMT) is unclear. Ectopic expression of miR-145 suppressed the proliferation, migration and invasion in SW480 but surprisingly enhanced these traits in its metastatic counterpart, SW620 cells, while, antimiR-145 reversed the effects of miR-145 in both of these human colorectal cancer cells. In SW480 and SW620 cells, SMAD-interacting protein 1 (SIP1), was identified as a target of miR-145, and its expression was suppressed both at mRNA and protein levels, and siRNA-SIP1 mimicked the effects of miR-145. Further, re-introduction of SIP1 alone or its co-expression with miR-145, rescued SW480 and SW620 cells from the effects of miR-145, indicating that the distinct functions of miR-145 might be mediated, in part, through SIP1. Since Wnt signaling plays an essential role in EMT in CRC progression, the effects of miR-145 on the expression of Wnt signaling intermediates and EMT markers were studied. Re-expression of miR-145 was found to downregulate the expression of CTNNB1, TCF4, CCND1, VIM, and SNAI, but, upregulated CDH1 expression in SW480 cells. On the other hand, miR-145 exhibited an oncogenic potential in SW620 cells by actuating Wnt signaling and the expression of EMT-relevant markers. These results strongly hint that the paradoxical functions of miR-145 in the regulation of proliferation, migration and invasion might be mediated through downregulation of SIP1, and differential tuning of Wnt signaling and EMT-mediators.
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Affiliation(s)
- Anusha Sathyanarayanan
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Karthik Subramanian Chandrasekaran
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
| | - Devarajan Karunagaran
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, India
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22
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Kumar AS, Rayala SK, Venkatraman G. Targeting IGF1R pathway in cancer with microRNAs: How close are we? RNA Biol 2018; 15:320-326. [PMID: 28613101 DOI: 10.1080/15476286.2017.1338240] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cancer of the head and neck are the most common cancers in India and account for 30% of all cancers. At molecular level, it could be attributed to the overexpression of growth factors like IGF1-R, EGFR, VEGF-R and deregulation of cell cycle regulators and tumor suppressors. IGF1-R is an emerging target in head and neck cancer treatment, because of its reported role in tumor development, progression and metastasis. IGF1R targeted agents are in advanced stages of clinical development. Nevertheless, these agents suffer from several disadvantages including acquired resistance and toxic side effects. Hence there is a need for developing newer agents targeting not only the receptor but also its downstream signaling. miRNAs are considered as master regulators of gene expression of multiple genes and has been widely reported to be a promising therapeutic strategy. This review discusses the present status of research in both these arenas and emphasizes the role of miRNA as a promising agent for biologic therapy.
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Affiliation(s)
- Arathy S Kumar
- a Department of Biotechnology , Indian Institute of Technology, Madras (IIT M) , Chennai , India
| | - Suresh K Rayala
- a Department of Biotechnology , Indian Institute of Technology, Madras (IIT M) , Chennai , India
| | - Ganesh Venkatraman
- b Department of Human Genetics , College of Biomedical Sciences, Technology & Research, Sri Ramachandra University , Porur, Chennai , India
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23
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Lupini L, Pepe F, Ferracin M, Braconi C, Callegari E, Pagotto S, Spizzo R, Zagatti B, Lanuti P, Fornari F, Ghasemi R, Mariani-Costantini R, Bolondi L, Gramantieri L, Calin GA, Sabbioni S, Visone R, Veronese A, Negrini M. Over-expression of the miR-483-3p overcomes the miR-145/TP53 pro-apoptotic loop in hepatocellular carcinoma. Oncotarget 2017; 7:31361-71. [PMID: 27120784 PMCID: PMC5058762 DOI: 10.18632/oncotarget.8913] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 04/10/2016] [Indexed: 01/01/2023] Open
Abstract
The miR-145-5p, which induces TP53-dependent apoptosis, is down-regulated in several tumors, including hepatocellular carcinomas (HCCs), but some HCCs show physiological expression of this miR. Here we demonstrate that in HCC cells carrying wild-type TP53 the steady activation of the miR-145 signaling selects clones resistant to apoptosis via up-regulation of the oncogenic miR-483-3p. Expression of the miR-145-5p and of the miR-483-3p correlated negatively in non-neoplastic liver (n=41; ρ=−0.342, P=0.028), but positively in HCCs (n=21; ρ=0.791, P<0.0001), which we hypothesized to be due to impaired glucose metabolism in HCCs versus normal liver. In fact, when liver cancer cells were grown in low glucose, miR-145-5p lowered miR-483-3p expression, allowing apoptosis, whereas when cells were grown in high glucose the levels of miR-483-3p increased, reducing the apoptotic rate. This indicates that depending on glucose availability the miR-145-5p has double effects on the miR-483-3p, either inhibitory or stimulatory. Moreover, resistance to apoptosis in clones overexpressing both miR-145-5p and miR-483-3p was abrogated by silencing the miR-483-3p. Our data highlight a novel mechanism of resistance to apoptosis in liver cancer cells harbouring wild type TP53 and suggest a potential role of miR-145-5p and miR-483-3p as druggable targets in a subset of HCCs.
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Affiliation(s)
- Laura Lupini
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Felice Pepe
- Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.,Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy
| | - Manuela Ferracin
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Chiara Braconi
- Division of Cancer Therapeutics, Institute of Cancer Research, London, UK
| | - Elisa Callegari
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Sara Pagotto
- Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.,Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy
| | | | - Barbara Zagatti
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Paola Lanuti
- Department of Medicine and Aging Science, G. d'Annunzio University, Chieti, Italy
| | | | - Reza Ghasemi
- Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy
| | - Renato Mariani-Costantini
- Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.,Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy
| | - Luigi Bolondi
- S.Orsola-Malpighi University Hospital, Bologna, Italy
| | | | - George A Calin
- Department of Experimental Therapeutics, MD Anderson Medical Centre, Houston, TX, USA
| | - Silvia Sabbioni
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Rosa Visone
- Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.,Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy
| | - Angelo Veronese
- Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.,Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy
| | - Massimo Negrini
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy
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24
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Tan W, Liu B, Qu S, Liang G, Luo W, Gong C. MicroRNAs and cancer: Key paradigms in molecular therapy. Oncol Lett 2017; 15:2735-2742. [PMID: 29434998 DOI: 10.3892/ol.2017.7638] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Accepted: 02/07/2017] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are a type of small non-coding RNA molecule that performs an important role in post-transcriptional gene regulation. Since miRNAs were first identified in 1993, a number of studies have demonstrated that they act as tumor suppressors or oncogenes in human cancer, including colorectal, lung, brain, breast and liver cancer, and leukemia. Large high-throughput studies have previously revealed that miRNA profiling is critical for the diagnosis and prognosis of patients with cancer, while certain miRNAs possess the potential to be used as diagnostic and prognostic biomarkers or therapeutic targets in cancer. The present study reviews the studies and examines the roles of miRNAs in cancer diagnosis, prognosis and treatment, and discusses the potential therapeutic modality of exploiting miRNAs.
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Affiliation(s)
- Weige Tan
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China.,Department of Breast Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 51000, P.R. China
| | - Bodu Liu
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Shaohua Qu
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Gehao Liang
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Wei Luo
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Chang Gong
- Breast Tumor Center and Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China
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25
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Prognostic value of microRNAs in hepatocellular carcinoma: a meta-analysis. Oncotarget 2017; 8:107237-107257. [PMID: 29291025 PMCID: PMC5739810 DOI: 10.18632/oncotarget.20883] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 08/29/2017] [Indexed: 12/20/2022] Open
Abstract
Background Numerous articles reported that dysregulated expression levels of miRNAs correlated with survival time of HCC patients. However, there has not been a comprehensive meta-analysis to evaluate the accurate prognostic value of miRNAs in HCC. Design Meta-analysis. Materials and Methods Studies, published in English, estimating expression levels of miRNAs with any survival curves in HCC were identified up until 15 April, 2017 by performing online searches in PubMed, EMBASE, Web of Science and Cochrane Database of Systematic Reviews by two independent authors. The pooled hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate the correlation between miRNA expression and overall survival (OS). Results 54 relevant articles about 16 miRNAs, with 6464 patients, were ultimately included. HCC patients with high expression of tissue miR-9 (HR = 2.35, 95% CI = 1.46–3.76), miR-21 (HR = 1.76, 95% CI = 1.29–2.41), miR-34c (HR = 1.64, 95% CI = 1.05–2.57), miR-155 (HR = 2.84, 95% CI = 1.46–5.51), miR-221 (HR = 1.76, 95% CI = 1.02–3.04) or low expression of tissue miR-22 (HR = 2.29, 95% CI = 1.63–3.21), miR-29c (HR = 1.35, 95% CI = 1.10–1.65), miR-34a (HR = 1.84, 95% CI = 1.30–2.59), miR-199a (HR = 2.78, 95% CI = 1.89–4.08), miR-200a (HR = 2.64, 95% CI = 1.86–3.77), miR-203 (HR = 2.20, 95% CI = 1.61–3.00) have significantly poor OS (P < 0.05). Likewise, HCC patients with high expression of blood miR-21 (HR = 1.73, 95% CI = 1.07–2.80), miR-192 (HR = 2.42, 95% CI = 1.15–5.10), miR-224 (HR = 1.56, 95% CI = 1.14–2.12) or low expression of blood miR-148a (HR = 2.26, 95% CI = 1.11–4.59) have significantly short OS (P < 0.05). Conclusions In conclusion, tissue miR-9, miR-21, miR-22, miR-29c, miR-34a, miR-34c, miR-155, miR-199a, miR-200a, miR-203, miR-221 and blood miR-21, miR-148a, miR-192, miR-224 demonstrate significantly prognostic value. Among them, tissue miR-9, miR-22, miR-155, miR-199a, miR-200a, miR-203 and blood miR-148a, miR-192 are potential prognostic candidates for predicting OS in HCC.
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26
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Li YW, Chiang KY, Li YH, Wu SY, Liu W, Lin CR, Wu JL. MiR-145 mediates zebrafish hepatic outgrowth through progranulin A signaling. PLoS One 2017; 12:e0177887. [PMID: 28531199 PMCID: PMC5439702 DOI: 10.1371/journal.pone.0177887] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 05/04/2017] [Indexed: 12/25/2022] Open
Abstract
MicroRNAs (miRs) are mRNA-regulatory molecules that fine-tune gene expression and modulate both processes of development and tumorigenesis. Our previous studies identified progranulin A (GrnA) as a growth factor which induces zebrafish hepatic outgrowth through MET signaling. We also found that miR-145 is one of potential fine-tuning regulators of GrnA involved in embryonic hepatic outgrowth. The low level of miR-145 seen in hepatocarinogenesis has been shown to promote pathological liver growth. However, little is known about the regulatory mechanism of miR-145 in embryonic liver development. In this study, we demonstrate a significant decrease in miR-145 expression during hepatogenesis. We modulate miR-145 expression in zebrafish embryos by injection with a miR-145 mimic or a miR-145 hairpin inhibitor. Altered embryonic liver outgrowth is observed in response to miR-145 expression modulation. We also confirm a critical role of miR-145 in hepatic outgrowth by using whole-mount in situ hybridization. Loss of miR-145 expression in embryos results in hepatic cell proliferation, and vice versa. Furthermore, we demonstrate that GrnA is a target of miR-145 and GrnA-induced MET signaling is also regulated by miR-145 as determined by luciferase reporter assay and gene expression analysis, respectively. In addition, co-injection of GrnA mRNA with miR-145 mimic or MO-GrnA with miR-145 inhibitor restores the liver defects caused by dysregulation of miR-145 expression. In conclusion, our findings suggest an important role of miR-145 in regulating GrnA-dependent hepatic outgrowth in zebrafish embryonic development.
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Affiliation(s)
- Ya-Wen Li
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Keng-Yu Chiang
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
- Department of Life science, National Taiwan University, Taipei, Taiwan
| | - Yen-Hsing Li
- Department of Chemistry, Purdue University, West Lafayette, Indiana, United States of America
| | - Sung-Yu Wu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Wangta Liu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Ray Lin
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Jen-Leih Wu
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
- * E-mail:
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27
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Wang JY, Fang M, Boye A, Wu C, Wu JJ, Ma Y, Hou S, Kan Y, Yang Y. Interaction of microRNA-21/145 and Smad3 domain-specific phosphorylation in hepatocellular carcinoma. Oncotarget 2017; 8:84958-84973. [PMID: 29156696 PMCID: PMC5689586 DOI: 10.18632/oncotarget.17709] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 04/02/2017] [Indexed: 12/27/2022] Open
Abstract
MicroRNAs 21 and 145 exhibit inverse expression in Hepatocellular carcinoma (HCC), but how they relate to Smad3 C-terminal and Link region phosphorylation (pSmad3C and pSmad3L) downstream of TGF-β/MAPK signaling, remains inconclusive. Our results suggest microRNA-145 targets Smad3 in HepG2 cells. Decreased tumor volume and increased apoptosis were produced in both microRNA-21 antagomir and microRNA-145 agomir groups compared to controls. Inhibition of TβRI and MAPK (ERK, JNK, and p38) activation respectively produced decreased microRNA-21 but increased microRNA-145 expression. Correspondingly, the expression level of pSmad3C obviously increased while pSmad3L decreased in microRNA-145 agomir-group and the expression of pSmad3C/3L were not markedly changed but pERK, pJNK, pp38 decreased in microRNA-21 antagomir-group compared to controls. On the other hand, microRNA-145 and 21 increased respectively in xenografts of HepG2 cells transfected with Smad3 EPSM and 3S-A plasmid, and this correlated with the overexpression of pSmad3C and pSmad3L respectively compared to control. To conclude, microRNA-21 promotes tumor progression in a MAPK-dependent manner while microRNA-145 suppresses it via domain-specific phosphorylation of Smad3 in HCC. Meanwhile, increased pSmad3C/3L lead to the up-regulation of microRNA-145/21 respectively. The interaction between pSmad3C/3L and microRNA-145/21 regulates HCC progression and the switch of pSmad3C/3L may serve as an important target for HCC therapy.
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Affiliation(s)
- Ji Yu Wang
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, China
| | - Meng Fang
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, China
| | - Alex Boye
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, China
| | - Chao Wu
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, China
| | - Jia Jun Wu
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, China
| | - Ying Ma
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, China
| | - Shu Hou
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, China
| | - Yue Kan
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, China
| | - Yan Yang
- Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, China
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28
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Micó V, Berninches L, Tapia J, Daimiel L. NutrimiRAging: Micromanaging Nutrient Sensing Pathways through Nutrition to Promote Healthy Aging. Int J Mol Sci 2017; 18:E915. [PMID: 28445443 PMCID: PMC5454828 DOI: 10.3390/ijms18050915] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Revised: 04/10/2017] [Accepted: 04/24/2017] [Indexed: 01/09/2023] Open
Abstract
Current sociodemographic predictions point to a demographic shift in developed and developing countries that will result in an unprecedented increase of the elderly population. This will be accompanied by an increase in age-related conditions that will strongly impair human health and quality of life. For this reason, aging is a major concern worldwide. Healthy aging depends on a combination of individual genetic factors and external environmental factors. Diet has been proved to be a powerful tool to modulate aging and caloric restriction has emerged as a valuable intervention in this regard. However, many questions about how a controlled caloric restriction intervention affects aging-related processes are still unanswered. Nutrient sensing pathways become deregulated with age and lose effectiveness with age. These pathways are a link between diet and aging. Thus, fully understanding this link is a mandatory step before bringing caloric restriction into practice. MicroRNAs have emerged as important regulators of cellular functions and can be modified by diet. Some microRNAs target genes encoding proteins and enzymes belonging to the nutrient sensing pathways and, therefore, may play key roles in the modulation of the aging process. In this review, we aimed to show the relationship between diet, nutrient sensing pathways and microRNAs in the context of aging.
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Affiliation(s)
- Víctor Micó
- Nutritional Genomics of Cardiovascular Disease and Obesity Fundation IMDEA Food, CEI UAM + CSIC, 28049 Madrid, Spain.
| | - Laura Berninches
- Nutritional Genomics of Cardiovascular Disease and Obesity Fundation IMDEA Food, CEI UAM + CSIC, 28049 Madrid, Spain.
| | - Javier Tapia
- Nutritional Genomics of Cardiovascular Disease and Obesity Fundation IMDEA Food, CEI UAM + CSIC, 28049 Madrid, Spain.
| | - Lidia Daimiel
- Nutritional Genomics of Cardiovascular Disease and Obesity Fundation IMDEA Food, CEI UAM + CSIC, 28049 Madrid, Spain.
- Department of Nutrition and Bromatology, CEU San Pablo University, Boadilla del Monte, 28668 Madrid, Spain.
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29
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Tunissiolli NM, Castanhole-Nunes MMU, Biselli-Chicote PM, Pavarino ÉC, da Silva RF, da Silva RDCMA, Goloni-Bertollo EM. Hepatocellular Carcinoma: a Comprehensive Review of
Biomarkers, Clinical Aspects, and Therapy. Asian Pac J Cancer Prev 2017; 18:863-872. [PMID: 28545181 PMCID: PMC5494234 DOI: 10.22034/apjcp.2017.18.4.863] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a cause of several deaths related to cancer worldwidely. In early stage, curative treatments such as surgical resection, liver transplant and local ablation can improve the patient ´s survival. However, the disease is detected in advanced stage; moreover some available therapies are restricted to palliative care and local treatment. Early detections of HCC and adequate therapy are crucial to increase survival as well as to improve the patient´s quality of life. Therefore, researchers have been investigating molecular biomarkers with high sensibility and reliability as Golgi 73 protein (GP73), Glypican-3 (GPC3), Osteopontin (OPN), microRNAs and others. MicroRNAs can regulate important pathways on carcinogenesis, as tumor angiogenesis and progression. So, they can be considered as possible markers of prognosis in HCC, and therapeutic target for this tumor type. In this review, we discuss the recent advances related to the cause (highlighting the main risk factors), treatment, biomarkers, clinic aspects, and outcome in hepatocellular carcinoma.
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Affiliation(s)
- Nathalia Martines Tunissiolli
- Research Unit of Genetics and Molecular Biology (UPGEM), São José do Rio Preto Medical School (FAMERP), São José do Rio Preto- SP, Brazil
- Liver Tumors Study Group (GETF),São Jose do Rio Preto Medical
School (FAMERP), Sao Jose do Rio Preto- SP, Brazil.
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30
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Yang Z, Li J, Feng G, Gao S, Wang Y, Zhang S, Liu Y, Ye L, Li Y, Zhang X. MicroRNA-145 Modulates N6-Methyladenosine Levels by Targeting the 3'-Untranslated mRNA Region of the N6-Methyladenosine Binding YTH Domain Family 2 Protein. J Biol Chem 2017; 292:3614-3623. [PMID: 28104805 DOI: 10.1074/jbc.m116.749689] [Citation(s) in RCA: 224] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 01/14/2017] [Indexed: 12/21/2022] Open
Abstract
N6-Methyladenosine (m6A) is a prevalent modification present in the mRNAs of higher eukaryotes. YTH domain family 2 (YTHDF2), an m6A "reader" protein, can recognize mRNA m6A sites to mediate mRNA degradation. However, the regulatory mechanism of YTHDF2 is poorly understood. To this end, we investigated the post-transcriptional regulation of YTHDF2. Bioinformatics analysis suggested that the microRNA miR-145 might target the 3'-untranslated region (3'-UTR) of YTHDF2 mRNA. The levels of miR-145 were negatively correlated with those of YTHDF2 mRNA in clinical hepatocellular carcinoma (HCC) tissues, and immunohistochemical staining revealed that YTHDF2 was closely associated with malignancy of HCC. Interestingly, miR-145 decreased the luciferase activities of 3'-UTR of YTHDF2 mRNA. Mutation of predicted miR-145 binding sites in the 3'-UTR of YTHDF2 mRNA abolished the miR-145-induced decrease in luciferase activity. Overexpression of miR-145 dose-dependently down-regulated YTHDF2 expression in HCC cells at the levels of both mRNA and protein. Conversely, inhibition of miR-145 resulted in the up-regulation of YTHDF2 in the cells. Dot blot analysis and immunofluorescence staining revealed that the overexpression of miR-145 strongly increased m6A levels relative to those in control HCC cells, and this increase could be blocked by YTHDF2 overexpression. Moreover, miR-145 inhibition strongly decreased m6A levels, which were rescued by treatment with a small interfering RNA-based YTHDF2 knockdown. Thus, we conclude that miR-145 modulates m6A levels by targeting the 3'-UTR of YTHDF2 mRNA in HCC cells.
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Affiliation(s)
- Zhe Yang
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Jiong Li
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Guoxing Feng
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Shan Gao
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Yuan Wang
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Shuqin Zhang
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Yunxia Liu
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China
| | - Lihong Ye
- State Key Laboratory of Medicinal Chemical Biology, Department of Biochemistry, College of Life Sciences, Nankai University, Tianjin 300071, China, and
| | - Yueguo Li
- Department of Clinical Laboratory, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China
| | - Xiaodong Zhang
- From the State Key Laboratory of Medicinal Chemical Biology, Department of Cancer Research, College of Life Sciences, Nankai University, Tianjin 300071, China,
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Youness RA, El-Tayebi HM, Assal RA, Hosny K, Esmat G, Abdelaziz AI. MicroRNA-486-5p enhances hepatocellular carcinoma tumor suppression through repression of IGF-1R and its downstream mTOR, STAT3 and c-Myc. Oncol Lett 2016; 12:2567-2573. [PMID: 27698829 PMCID: PMC5038225 DOI: 10.3892/ol.2016.4914] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 06/16/2016] [Indexed: 12/25/2022] Open
Abstract
The insulin-like growth factor (IGF)-axis has been paradigmatically involved in hepatocellular carcinoma (HCC) tumor initiation, progression and drug resistance. Consequently, members of the IGF-axis and most importantly, IGF-1 receptor (IGF-1R) have been considered as intriguing targets for HCC therapy. Few miRNAs have been recently reported to be associated with IGF-1R regulation. The present study aimed to investigate the role of microRNA (miRNA/miR)-486-5p in the regulation of IGF-1R and its downstream signaling cascades. miR-486-5p was markedly downregulated in hepatitis C virus-induced HCC tissues and Huh-7 cells. Forcing the expression of miR-486-5p in Huh-7 cells resulted in the repression of IGF-1R, mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3) and c-Myc mRNA levels. Ectopic expression of miR-486-5p in Huh-7 cells markedly repressed cellular viability, proliferation, migration and clonogenicity in a similar pattern to IGF-1R small interfering RNAs, and were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, BrdU incorporation, wound healing and colony forming assays, respectively. Overall, the study findings demonstrated that miR-486-5p acts as a tumor suppressor in HCC through the repression of essential members of the IGF-axis, including IGF-1R and its downstream mediators mTOR, STAT3 and c-Myc.
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Affiliation(s)
- Rana Ahmed Youness
- Department of Pharmaceutical Biology, Faculty of Pharmacy and Biotechnology, German University in Cairo, New Cairo City, Cairo 11835, Egypt
| | - Hend Mohamed El-Tayebi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, New Cairo City, Cairo 11835, Egypt
| | - Reem Amr Assal
- Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, New Cairo City, Cairo 11835, Egypt
| | - Karim Hosny
- Department of General Surgery, Faculty of Medicine, Cairo University, Giza 12613, Egypt
| | - Gamal Esmat
- Department of Endemic Medicine and Hepatology, Cairo University, Giza 12613, Egypt
| | - Ahmed Ihab Abdelaziz
- Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, German University in Cairo, New Cairo City, Cairo 11835, Egypt
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Liu X, Li J, Yu Z, Li J, Sun R, Kan Q. miR-935 Promotes Liver Cancer Cell Proliferation and Migration by Targeting SOX7. Oncol Res 2016; 25:427-435. [PMID: 27697092 PMCID: PMC7841071 DOI: 10.3727/096504016x14747300207374] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common cancer in the world. MicroRNAs (miRNAs) are a type of small noncoding RNA that can regulate the expression of target genes under physiological and pathophysiological conditions. Aberrant expression of microRNA-935 (miR-935) has been reported in cancer studies. However, its expression and mechanism in HCC remain unclear. In our study, we found that miR-935 was upregulated in liver cancer tissues and cells. Overexpression of miR-935 in liver cells promoted cell proliferation, tumorigenesis, and cell cycle progression, whereas inhibition of miR-935 reduced cell proliferation, tumorigenicity, and cell cycle progression. These changes in the properties of HCC cells were associated with upregulation of two well-known cellular G1/S transitional regulators: cyclin D1 and c-Myc. Additionally, we identified SOX7 as a direct target of miR-935. Overexpression of miR-935 inhibited SOX7 expression but promoted the levels of c-Myc and cyclin D1, which promotes cell proliferation and tumorigenesis; knockdown of miR-935 increased SOX7 level and inhibited c-Myc and cyclin D1 expression, whereas SOX7 silencing could promote cell proliferation, cell motility, and invasiveness in vitro. Our findings suggest that miR-935 represents a biomarker and a potential new target in HCC progression by suppressing SOX7 expression.
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Sun K, Wang J, Liu F, Ji Z, Guo Z, Zhang C, Yao M. Ossotide promotes cell differentiation of human osteoblasts from osteogenesis imperfecta patients by up-regulating miR-145. Biomed Pharmacother 2016; 83:1105-1110. [PMID: 27551756 DOI: 10.1016/j.biopha.2016.08.025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Revised: 07/20/2016] [Accepted: 08/09/2016] [Indexed: 01/01/2023] Open
Abstract
Ossotide as an effective bone formation compound preparation has been proved to promote osteoblasts differentiation. MiR-145 is significantly decreased in osteogenesis imperfecta (OI) patients, but it is still unknown whether ossotide performed its effect by regulating miR-145. In this study, we investigated the effect of ossotide on regulating miR-145 expression and osteoblasts differentiation. The primary osteoblasts cells were isolated from OI patients and then cultured with different concentrations (0, 25, 50, 100, 200μg/l) of ossotide. The cell proliferation was detected with CCK-8 Elisa kit after ossotide treatment. The level of miR-145 expression was determined using qRT-PCR. In order to study whether ossotide up regulated miR-145, miR-145 mimic and miR-145 inhibitor were used to up regulate and down regulate the miR-145 levels in osteoblasts. The expressions of Runx2, Osx, β-catenin, TCF-1 were detected using Western blot and qRT-PCR. We observed that miR-145 was up regulated by ossotide treatment in miR-145 mimic or miR-145 inhibitor treated osteoblasts. What's more, up regulated miR-145 increased the expression of osteoblasts differentiation regulated protein Runx2 and Osx. In addition, Wnt signaling related β-catenin, TCF-1 were activated by up-regulated miR-145 which was induced by ossotide treatment. In summary, ossotide induced cell differentiation and Wnt signaling activation in osteoblasts by up regulating miR-145.
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Affiliation(s)
- Keming Sun
- Department of Pediatric Orthopedics, Zhengzhou Children's Hospital, Zhengzhou, Henan 450000, China
| | - Junjian Wang
- Department of Pediatric Orthopedics, Zhengzhou Children's Hospital, Zhengzhou, Henan 450000, China
| | - Fangna Liu
- Department of Pediatric Orthopedics, Zhengzhou Children's Hospital, Zhengzhou, Henan 450000, China
| | - Zejuan Ji
- Department of Pediatric Orthopedics, Zhengzhou Children's Hospital, Zhengzhou, Henan 450000, China
| | - Zhanhao Guo
- Department of Pediatric Orthopedics, Zhengzhou Children's Hospital, Zhengzhou, Henan 450000, China
| | - Chunxu Zhang
- Department of Pediatric Orthopedics, Zhengzhou Children's Hospital, Zhengzhou, Henan 450000, China
| | - Manye Yao
- Department of Pediatric Orthopedics, Zhengzhou Children's Hospital, Zhengzhou, Henan 450000, China.
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miR-195 inhibits tumor growth and angiogenesis through modulating IRS1 in breast cancer. Biomed Pharmacother 2016; 80:95-101. [DOI: 10.1016/j.biopha.2016.03.007] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 03/08/2016] [Accepted: 03/08/2016] [Indexed: 11/22/2022] Open
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El Tayebi HM, Abdelaziz AI. Epigenetic regulation of insulin-like growth factor axis in hepatocellular carcinoma. World J Gastroenterol 2016; 22:2668-2677. [PMID: 26973407 PMCID: PMC4777991 DOI: 10.3748/wjg.v22.i9.2668] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/29/2015] [Accepted: 12/08/2015] [Indexed: 02/06/2023] Open
Abstract
The insulin-like growth factor (IGF) signaling pathway is an important pathway in the process of hepatocarcinogenesis, and the IGF network is clearly dysregulated in many cancers and developmental abnormalities. In hepatocellular carcinoma (HCC), only a minority of patients are eligible for curative treatments, such as tumor resection or liver transplant. Unfortunately, there is a high recurrence of HCC after surgical tumor removal. Recent research efforts have focused on targeting IGF axis members in an attempt to find therapeutic options for many health problems. In this review, we shed lights on the regulation of members of the IGF axis, mainly by microRNAs in HCC. MicroRNAs in HCC attempt to halt the aberrant expression of the IGF network, and a single microRNA can have multiple downstream targets in one or more signaling pathways. Targeting microRNAs is a relatively new approach for identifying an efficient radical cure for HCC.
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Wang Y, Tian Y. miRNA for diagnosis and clinical implications of human hepatocellular carcinoma. Hepatol Res 2016; 46:89-99. [PMID: 26284466 DOI: 10.1111/hepr.12571] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 06/12/2015] [Accepted: 08/10/2015] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies, as a result of being asymptomatic at early stage, subsequent late clinical confirmation and poor prognosis. It is urgent to search more accurate biomarkers for diagnosing early HCC and predicting prognosis. Many factors participate in liver carcinogenesis, including dysregulation of miRNA. miRNA were endogenously expressed non-coding single-stranded small RNA with 19-25 nucleotides. Accumulating evidences have showed that miRNA from circulation and solitary tumors may be useful to classify the differentiation degree and stages of HCC, detect the hepatitis B/C virus-related HCC, and predict the survival rate after surgical resection or orthotopic liver transplantation. In this review, we summarize dysregulated miRNA, their roles in diagnosis and clinical implications of HCC.
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Affiliation(s)
- Yurong Wang
- Core Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Yaping Tian
- Core Laboratory of Translational Medicine, Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
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Fujii T, Shimada K, Tatsumi Y, Hatakeyama K, Obayashi C, Fujimoto K, Konishi N. microRNA-145 promotes differentiation in human urothelial carcinoma through down-regulation of syndecan-1. BMC Cancer 2015; 15:818. [PMID: 26514209 PMCID: PMC4625524 DOI: 10.1186/s12885-015-1846-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 10/23/2015] [Indexed: 01/01/2023] Open
Abstract
Background A new molecular marker of carcinoma in the urinary bladder is needed as a diagnostic tool or as a therapeutic target. Potential markers include microRNAs (miRNAs), which are short, low molecular weight RNAs 19–24 nt long that regulate genes associated with cell proliferation, differentiation, and development in various cancers. In this study, we investigated the molecular mechanisms by which miR-145 promotes survival of urothelial carcinoma cells and differentiation into multiple lineages. We found miR-145 to regulate expression of syndecan-1, a heparin sulfate proteoglycan. Methods Cell proliferation in the human urothelial carcinoma cell lines T24 and KU7 was assessed by MTS assay. Cellular senescence and apoptosis were measured by senescence-associated β-galactosidase (SA-β-gal) and TUNEL assay, respectively. Quantitative RT-PCR was used to measure mRNA expression of various genes, including syndecan-1, stem cell factors, and markers of differentiation into squamous, glandular, or neuroendocrine cells. Results Overexpression of miR-145 induced cell senescence, and thus significantly inhibited cell proliferation in T24 and KU7 cells. Syndecan-1 expression diminished, whereas stem cell markers such as SOX2, NANOG, OCT4, and E2F3 increased. miR-145 also up-regulated markers of differentiation into squamous (p63, TP63, and CK5), glandular (MUC-1, MUC-2, and MUC-5 AC), and neuroendocrine cells (NSE and UCHL-1). Finally, expression of miR-145 was down-regulated in high-grade urothelial carcinomas, but not in low-grade tumors. Conclusions Results indicate that miR-145 suppresses syndecan-1 and, by this mechanism, up-regulates stem cell factors and induces cell senescence and differentiation. We propose that miR-145 may confer stem cell-like properties on urothelial carcinoma cells and thus facilitate differentiation into multiple cell types. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1846-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tomomi Fujii
- Department of Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
| | - Keiji Shimada
- Department of Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
| | - Yoshihiro Tatsumi
- Department of Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan. .,Department of Urology, Nara Medical University School of Medicine, Nara, Japan.
| | - Kinta Hatakeyama
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, Nara, Japan.
| | - Chiho Obayashi
- Department of Diagnostic Pathology, Nara Medical University School of Medicine, Nara, Japan.
| | - Kiyohide Fujimoto
- Department of Urology, Nara Medical University School of Medicine, Nara, Japan.
| | - Noboru Konishi
- Department of Pathology, Nara Medical University School of Medicine, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
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Das AV, Pillai RM. Implications of miR cluster 143/145 as universal anti-oncomiRs and their dysregulation during tumorigenesis. Cancer Cell Int 2015; 15:92. [PMID: 26425114 PMCID: PMC4588501 DOI: 10.1186/s12935-015-0247-4] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 09/22/2015] [Indexed: 02/07/2023] Open
Abstract
Tumorigenesis is a multistep process, de-regulated due to the imbalance of oncogenes as well as anti-oncogenes, resulting in disruption of tissue homeostasis. In many cases the effect of oncogenes and anti-oncogenes are mediated by various other molecules such as microRNAs. microRNAs are small non-coding RNAs established to post-transcriptionally regulate more than half of the protein coding genes. miR cluster 143/145 is one such cancer-related microRNA cluster which is down-regulated in most of the cancers and is able to hinder tumorigenesis by targeting tumor-associated genes. The fact that they could sensitize drug-resistant cancer cells by targeting multidrug resistant genes makes them potent tools to target cancer cells. Their low levels precede events which lead to cancer progression and therefore could be considered also as biomarkers to stage the disease. Interestingly, evidence suggests the existence of several in vivo mechanisms by which this cluster is differentially regulated at the molecular level to keep their levels low in cancer. In this review, we summarize the roles of miR cluster 143/145 in cancer, their potential prognostic applications and also their regulation during tumorigenesis.
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Affiliation(s)
- Ani V Das
- Cancer Research Program-9, Rajiv Gandhi Centre for Biotechnology, Thycaud.P.O., Thiruvananthapuram-14, Kerala India
| | - Radhakrishna M Pillai
- Cancer Research Program-9, Rajiv Gandhi Centre for Biotechnology, Thycaud.P.O., Thiruvananthapuram-14, Kerala India
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39
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Khanmi K, Ignacimuthu S, Paulraj MG. MicroRNA in prostate cancer. Clin Chim Acta 2015; 451:154-60. [PMID: 26415820 DOI: 10.1016/j.cca.2015.09.022] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 09/21/2015] [Accepted: 09/23/2015] [Indexed: 12/17/2022]
Abstract
In the United States of America male prostate cancer (PCa) is the most dominant malignancy and the second highest cause of cancer-related mortality risk compared to lung and colon cancers. MicroRNAs (miRNAs) are a class of endogenously expressed small, non-coding, single-stranded RNA which function as regulators of gene expression. They influence various physiological and pathophysiological processes. In this review, we focus on the regulation of miRNAs in prostate cancer and their mechanisms which contribute to prostate carcinogenesis. The relation of miRNAs with androgen signaling is highlighted and the prospects of miRNAs for clinical therapies are discussed.
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Affiliation(s)
- Kasomva Khanmi
- Molecular Biology Unit, Entomology Research Institute, Loyola College, Nungambakkam, Chennai 600 034, India
| | - Savarimuthu Ignacimuthu
- Molecular Biology Unit, Entomology Research Institute, Loyola College, Nungambakkam, Chennai 600 034, India; Visiting Professor Programme, Deanship of Scientific Research, College of Science, King Saud University, Saudi Arabia.
| | - Michael Gabriel Paulraj
- Molecular Biology Unit, Entomology Research Institute, Loyola College, Nungambakkam, Chennai 600 034, India
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Jagannathan R, Thapa D, Nichols CE, Shepherd DL, Stricker JC, Croston TL, Baseler WA, Lewis SE, Martinez I, Hollander JM. Translational Regulation of the Mitochondrial Genome Following Redistribution of Mitochondrial MicroRNA in the Diabetic Heart. ACTA ACUST UNITED AC 2015; 8:785-802. [PMID: 26377859 DOI: 10.1161/circgenetics.115.001067] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 09/01/2015] [Indexed: 01/05/2023]
Abstract
BACKGROUND Cardiomyocytes are rich in mitochondria which are situated in spatially distinct subcellular regions, including those under the plasma membrane, subsarcolemmal mitochondria, and those between the myofibrils, interfibrillar mitochondria. We previously observed subpopulation-specific differences in mitochondrial proteomes following diabetic insult. The objective of this study was to determine whether mitochondrial genome-encoded proteins are regulated by microRNAs inside the mitochondrion and whether subcellular spatial location or diabetes mellitus influences the dynamics. METHODS AND RESULTS Using microarray technology coupled with cross-linking immunoprecipitation and next generation sequencing, we identified a pool of mitochondrial microRNAs, termed mitomiRs, that are redistributed in spatially distinct mitochondrial subpopulations in an inverse manner following diabetic insult. Redistributed mitomiRs displayed distinct interactions with the mitochondrial genome requiring specific stoichiometric associations with RNA-induced silencing complex constituents argonaute-2 (Ago2) and fragile X mental retardation-related protein 1 (FXR1) for translational regulation. In the presence of Ago2 and FXR1, redistribution of mitomiR-378 to the interfibrillar mitochondria following diabetic insult led to downregulation of mitochondrially encoded F0 component ATP6. Next generation sequencing analyses identified specific transcriptome and mitomiR sequences associated with ATP6 regulation. Overexpression of mitomiR-378 in HL-1 cells resulted in its accumulation in the mitochondrion and downregulation of functional ATP6 protein, whereas antagomir blockade restored functional ATP6 protein and cardiac pump function. CONCLUSIONS We propose mitomiRs can translationally regulate mitochondrially encoded proteins in spatially distinct mitochondrial subpopulations during diabetes mellitus. The results reveal the requirement of RNA-induced silencing complex constituents in the mitochondrion for functional mitomiR translational regulation and provide a connecting link between diabetic insult and ATP synthase function.
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Affiliation(s)
- Rajaganapathi Jagannathan
- From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown
| | - Dharendra Thapa
- From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown
| | - Cody E Nichols
- From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown
| | - Danielle L Shepherd
- From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown
| | - Janelle C Stricker
- From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown
| | - Tara L Croston
- From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown
| | - Walter A Baseler
- From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown
| | - Sara E Lewis
- From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown
| | - Ivan Martinez
- From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown
| | - John M Hollander
- From the Department of Human Performances, Division of Exercise Physiology (R.J., D.T., C.E.N., D.L.S., J.C.S., T.L.C., W.A.B., S.E.L., J.M.H.), Center for Cardiovascular and Respiratory Sciences (R.J., D.T., C.E.N., D.L.S., T.L.C., W.A.B., S.E.L., J.M.H.), Department of Microbiology, Immunology and Cell Biology (I.M.), and Mary Babb Randolph Cancer Center (I.M.), West Virginia University School of Medicine, Morgantown.
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Liu Y, Zhu ST, Wang X, Deng J, Li WH, Zhang P, Liu BS. MiR-100 Inhibits Osteosarcoma Cell Proliferation, Migration, and Invasion and Enhances Chemosensitivity by Targeting IGFIR. Technol Cancer Res Treat 2015; 15:NP40-8. [PMID: 26306402 DOI: 10.1177/1533034615601281] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2014] [Accepted: 07/22/2015] [Indexed: 01/29/2023] Open
Abstract
MicroRNAs are highly conserved noncoding RNA that negatively modulate protein expression at a posttranscriptional and/or translational level. MicroRNAs play an important role in the development and progression of human cancers, including osteosarcoma. Recent studies have shown that miR-100 was downregulated in many cancers; however, the role of miR-100 in human osteosarcoma has not been totally elucidated. In this study, we demonstrate that the expression of miR-100 was significantly downregulated in human osteosarcoma tissues compared to the adjacent tissues. Enforced expression of miR-100 inhibited cell proliferation, migration, and invasion abilities of osteosarcoma cells, U-2OS, and MG-63. Additionally, miR-100 also sensitized osteosarcoma cells to cisplatin and promoted apoptosis. Furthermore, overexpression of miR-100 decreased the expression of insulin-like growth factor I receptor and inhibited PI3K/AKT and MAPK/ERK signaling. In human clinical specimens, insulin-like growth factor I receptor was inversely correlated with miR-100 in osteosarcoma tissues. Collectively, our results demonstrate that miR-100 is a tumor suppressor microRNA and indicate its potential application for the treatment of osteosarcoma in future.
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Affiliation(s)
- Yang Liu
- Department of Orthopedics, Huaihe Hospital of Henan University, Kaifeng, China
| | - Shu-Tao Zhu
- Department of Orthopedics, Huaihe Hospital of Henan University, Kaifeng, China
| | - Xiao Wang
- Department of Orthopedics, Huaihe Hospital of Henan University, Kaifeng, China
| | - Jun Deng
- Department of Orthopedics, Huaihe Hospital of Henan University, Kaifeng, China
| | - Wei-Hua Li
- Department of Orthopedics, Huaihe Hospital of Henan University, Kaifeng, China
| | - Peng Zhang
- Department of Orthopedics, Huaihe Hospital of Henan University, Kaifeng, China
| | - Bing-Shan Liu
- Department of Orthopedics, Huaihe Hospital of Henan University, Kaifeng, China
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miRNA-based therapies: strategies and delivery platforms for oligonucleotide and non-oligonucleotide agents. Future Med Chem 2015; 6:1967-84. [PMID: 25495987 DOI: 10.4155/fmc.14.116] [Citation(s) in RCA: 218] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The discovery of miRNAs as important regulatory agents for gene expression has expanded the therapeutic opportunities for oligonucleotides. In contrast to siRNA, miRNA-targeted therapy is able to influence not only a single gene, but entire cellular pathways or processes. It is possible to supplement downregulated or non-functional miRNAs by synthetic oligonucleotides, as well as alleviating effects caused by overexpression of malignant miRNAs through artificial antagonists, either oligonucleotides or small molecules. Chemical oligonucleotide modifications together with an efficient delivery system seem to be mandatory for successful therapeutic application. While miRNA-based therapy benefits from the decades of research spent on other therapeutic oligonucleotides, there are some specific challenges associated with miRNA therapy, mainly caused by the short target sequence. The current status and recent progress of miRNA-targeted therapeutics is described and future challenges and potential applications in treatment of cancer and viral infections are discussed.
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Song JL, Nigam P, Tektas SS, Selva E. microRNA regulation of Wnt signaling pathways in development and disease. Cell Signal 2015; 27:1380-91. [PMID: 25843779 PMCID: PMC4437805 DOI: 10.1016/j.cellsig.2015.03.018] [Citation(s) in RCA: 101] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 03/24/2015] [Accepted: 03/24/2015] [Indexed: 12/19/2022]
Abstract
Wnt signaling pathways and microRNAs (miRNAs) are critical regulators of development. Aberrant Wnt signaling pathways and miRNA levels lead to developmental defects and diverse human pathologies including but not limited to cancer. Wnt signaling pathways regulate a plethora of cellular processes during embryonic development and maintain homeostasis of adult tissues. A majority of Wnt signaling components are regulated by miRNAs which are small noncoding RNAs that are expressed in both animals and plants. In animal cells, miRNAs fine tune gene expression by pairing primarily to the 3'untranslated region of protein coding mRNAs to repress target mRNA translation and/or induce target degradation. miRNA-mediated regulation of signaling transduction pathways is important in modulating dose-sensitive response of cells to signaling molecules. This review discusses components of the Wnt signaling pathways that are regulated by miRNAs in the context of development and diseases. A fundamental understanding of miRNA functions in Wnt signaling transduction pathways may yield new insight into crosstalks of regulatory mechanisms essential for development and disease pathophysiology leading to novel therapeutics.
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Affiliation(s)
- Jia L Song
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
| | - Priya Nigam
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Senel S Tektas
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
| | - Erica Selva
- Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA
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Lyra-González I, Flores-Fong LE, González-García I, Medina-Preciado D, Armendáriz-Borunda J. MicroRNAs dysregulation in hepatocellular carcinoma: Insights in genomic medicine. World J Hepatol 2015; 7:1530-1540. [PMID: 26085912 PMCID: PMC4462691 DOI: 10.4254/wjh.v7.i11.1530] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 12/22/2014] [Accepted: 05/11/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the leading primary liver cancer and its clinical outcome is still poor. MicroRNAs (miRNAs) have demonstrated an interesting potential to regulate gene expression at post-transcriptional level. Current findings suggest that miRNAs deregulation in cancer is caused by genetic and/or epigenetic, transcriptional and post-transcriptional modifications resulting in abnormal expression and hallmarks of malignant transformation: aberrant cell growth, cell death, differentiation, angiogenesis, invasion and metástasis. The important role of miRNAs in the development and progression of HCC has increased the efforts to understand and develop mechanisms of control overt this single-stranded RNAs. Several studies have analyzed tumoral response to the regulation and control of deregulated miRNAs with good results in vitro and in vivo, proving that targeting aberrant expression of miRNAs is a powerful anticancer therapeutic. Identification of up and/or down regulated miRNAs related to HCC has led to the discovery of new potential application for detection of their presence in the affected organism. MiRNAs represent a relevant new target for diagnosis, prognosis and treatment in a wide variety of pathologic entities, including HCC. This manuscript intends to summarize current knowledge regarding miRNAs and their role in HCC development.
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Avgeris M, Mavridis K, Tokas T, Stravodimos K, Fragoulis EG, Scorilas A. Uncovering the clinical utility of miR-143, miR-145 and miR-224 for predicting the survival of bladder cancer patients following treatment. Carcinogenesis 2015; 36:528-37. [PMID: 25804644 DOI: 10.1093/carcin/bgv024] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Accurate prognosis is a key factor in establishing optimal therapeutic decisions; yet in the case of bladder cancer (BlCa) current prognostic indicators cannot ensure optimal disease management. Here, we aimed to evaluate the previously unexplored clinical potential of the urological cancer-related miR-145, miR-143 and miR-224 in BlCa. A total of 279 bladder tissue specimens were included in this study (133 BlCa, 107 adjacent normal and 39 healthy samples). Total RNA was extracted from tissues, it was polyadenylated and reverse transcribed to cDNA. The expression of target molecules was measured via quantitative real-time PCR. The expression levels of both miR-143 and miR-145 were significantly decreased, whereas those of miR-224 were increased in BlCa. Receiver operating characteristic curve analysis indicated a significant discriminatory capacity for miR-143/miR-145 levels. Important associations with disease aggressiveness were observed for all three microRNAs; elevated levels were observed in tumors of higher stage and grade, as well as in 'high-risk' TaT1 patients. More importantly, high miR-143/145 levels could effectively prognose inferior overall survival for muscle-invasive patients and could independently predict the progression of superficial tumors. Finally, the combination of miR-143/145 overexpression with the widely used prognostic markers of European Organization for Research and Treatment of Cancer-risk groups or recurrence at the first follow-up cystoscopy resulted to a superior positive prediction of non-muscle-invasive bladder cancer short-term progression compared with the use of the abovementioned markers alone. The cancer-related miR-143, miR-145 and miR-224 were investigated for the first time in the clinical setting of BlCa, and miR-143/145 cluster constitutes a novel marker helpful for providing an enhanced prediction of oncologic outcome for BlCa patients.
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Affiliation(s)
- Margaritis Avgeris
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, 15701 Athens, Greece and First Department of Urology, "Laiko" General Hospital, Medical School, University of Athens, Agiou Thoma 17, 11527 Athens, Greece
| | - Konstantinos Mavridis
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, 15701 Athens, Greece and First Department of Urology, "Laiko" General Hospital, Medical School, University of Athens, Agiou Thoma 17, 11527 Athens, Greece
| | - Theodoros Tokas
- First Department of Urology, "Laiko" General Hospital, Medical School, University of Athens, Agiou Thoma 17, 11527 Athens, Greece
| | - Konstantinos Stravodimos
- First Department of Urology, "Laiko" General Hospital, Medical School, University of Athens, Agiou Thoma 17, 11527 Athens, Greece
| | - Emmanuel G Fragoulis
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, 15701 Athens, Greece and First Department of Urology, "Laiko" General Hospital, Medical School, University of Athens, Agiou Thoma 17, 11527 Athens, Greece
| | - Andreas Scorilas
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, 15701 Athens, Greece and First Department of Urology, "Laiko" General Hospital, Medical School, University of Athens, Agiou Thoma 17, 11527 Athens, Greece
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Wang C, Tao W, Ni S, Chen Q, Zhao Z, Ma L, Fu Y, Jiao Z. Tumor-suppressive microRNA-145 induces growth arrest by targeting SENP1 in human prostate cancer cells. Cancer Sci 2015; 106:375-82. [PMID: 25645686 PMCID: PMC4409880 DOI: 10.1111/cas.12626] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 01/23/2015] [Accepted: 01/28/2015] [Indexed: 12/22/2022] Open
Abstract
Prostate cancer (PCa) prevails as the most commonly diagnosed malignancy in men and the third leading cause of cancer-related deaths in developed countries. One of the distinct characteristics of prostate cancer is overexpression of the small ubiquitin-like modifier (SUMO)-specific protease 1 (SENP1), and the upregulation of SENP1 contributes to the malignant progression and cell proliferation of PCa. Previous studies have shown that the expression of microRNA-145 (miRNA-145) was extensively deregulated in PCa cell lines and primary clinical prostate cancer samples. Independent target prediction methods have indicated that the 3′-untranslated region of SENP1 mRNA is a potential target of miR-145. Here we found that low expression of miR-145 was correlated with high expression of SENP1 in PCa cell line PC-3. The transient introduction of miR-145 caused cell cycle arrest in PC-3 cells, and the opposite effect was observed when miR-145 inhibitor was transfected. Further studies revealed that the SENP1 3′-untranslated region was a regulative target of miR-145 in vitro. MicroRNA-145 also suppressed tumor formation in vivo in nude mice. Taken together, miR-145 plays an important role in tumorigenesis of PCa through interfering SENP1.
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Affiliation(s)
- Chunyang Wang
- Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Xu W, Huang H, Yu L, Cao L. Meta-analysis of gene expression profiles indicates genes in spliceosome pathway are up-regulated in hepatocellular carcinoma (HCC). Med Oncol 2015; 32:96. [DOI: 10.1007/s12032-014-0425-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2014] [Accepted: 11/29/2014] [Indexed: 11/25/2022]
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Zhang JY, Sun MY, Song NH, Deng ZL, Xue CY, Yang J. Prognostic role of microRNA-205 in multiple human malignant neoplasms: a meta-analysis of 17 studies. BMJ Open 2015; 5:e006244. [PMID: 25613953 PMCID: PMC4305071 DOI: 10.1136/bmjopen-2014-006244] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE MicroRNA-205 (miRNA-205) was revealed as an attractive prognostic tumour biomarker in recent studies. However, the results of different studies have been inconsistent. We conducted a meta-analysis to elucidate the precise predictive value of miRNA-205 in various human malignant neoplasms. DESIGN Meta-analysis. DATA SOURCES Qualified studies were identified up to 5 June 2014 by performing online searches in PubMed, EMBASE and Web of Science, and additional quality evaluations. PARTICIPANTS Seventeen eligible studies with 4827 patients were ultimately enrolled in this meta-analysis. OUTCOME MEASURES The heterogeneity between studies was assessed using I(2) statistics. Pooled HRs with 95% CIs for patient survival and disease recurrence were calculated to investigate the correlation between miRNA-205 expression and cancer prognosis. RESULTS Our results indicate that elevated miRNA-205 was significantly associated with enhanced overall survival in the breast cancer subgroup (HR=0.78, 95% CI 0.67 to 0.91) and superior disease-free survival/recurrence-free survival in the adenocarcinoma subgroup (HR=0.68, 95% CI 0.49 to 0.94). CONCLUSIONS miRNA-205 is a promising biomarker for predicting the recurrence and progression of patients with adenocarcinomas or breast cancer. Owing to its complex roles, further relevant studies are warranted.
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Affiliation(s)
- Jia-yi Zhang
- From Department of Urology, The First Affiliated Hospital Of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Meng-yan Sun
- From Department of Plastic Surgery, Changhai Hospital Affiliated To Second Military Medical University, Shanghai, China
| | - Ning-hong Song
- From Department of Urology, The First Affiliated Hospital Of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhong-lei Deng
- From Department of Urology, Affiliated Hospital Of Nanjing Medical University Of TCM,Nanjing, Jiangsu, China
| | - Chun-yu Xue
- From Department of Plastic Surgery, Changhai Hospital Affiliated To Second Military Medical University, Shanghai, China
| | - Jie Yang
- From Department of Urology, The First Affiliated Hospital Of Nanjing Medical University, Nanjing, Jiangsu, China
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Kang YJ, Lees M, Matthews LC, Kimber SJ, Forbes K, Aplin JD. MiR-145 suppresses embryo-epithelial juxtacrine communication at implantation by modulating maternal IGF1R. J Cell Sci 2015; 128:804-14. [PMID: 25609710 DOI: 10.1242/jcs.164004] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Successful implantation requires the synchronization of viable embryonic development with endometrial receptivity. The mechanisms allowing for the initiation of crosstalk between the embryo and the endometrium remain elusive; however, recent studies have revealed that there are alterations in endometrial microRNAs (miRs) in women suffering repeated implantation failure and that one of the altered miRs is miR-145. We assessed the role of miR-145 and its target IGF1R, in early implantation. miR-145 overexpression and IGF1R knockdown were achieved in Ishikawa endometrial cells. Quantitative PCR, western blotting and 3'UTR luciferase reporter assays confirmed that IGF1R is a direct target of miR-145 in the endometrium. Attachment of mouse embryos or IGF1-coated beads to endometrial epithelial cells was used to study the effects of altered miR-145 and/or IGF1R expression on early implantation events. miR-145 overexpression or specific reduction of IGF1R impaired attachment in both cases. An IGF1R target protector prevented the miR-145-mediated reduction in IGF1R and reversed the effect of miR-145 overexpression on attachment. The data demonstrate that miR-145 influences embryo attachment by reducing the level of IGF1R in endometrium.
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Affiliation(s)
- Youn-Jung Kang
- Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Level 3, Women's Centre, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
| | - Miranda Lees
- Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK
| | - Laura C Matthews
- Centre for Endocrinology & Diabetes, Institute of Human Development, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK
| | - Susan J Kimber
- Faculty of Life Sciences, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK
| | - Karen Forbes
- Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK
| | - John D Aplin
- Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester M13 9WL, UK St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK
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50
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Abstract
The insulin-like growth factor 1 (IGF-1) signaling pathway regulates critical biological processes including development, homeostasis, and aging. Dysregulation of this pathway has been implicated in a myriad of diseases such as cancers, neurodegenerative diseases, and metabolic disorders, making the IGF-1 signaling pathway a prime target to develop therapeutic and intervention strategies. Recently, small non-coding RNA molecules in ∼22 nucleotide length, microRNAs (miRNAs), have emerged as a new regulator of biological processes in virtually all organ systems and increasing studies are linking altered miRNA function to disease mechanisms. A miRNA binds to 3'UTRs of multiple target genes and coordinately downregulates their expression, thereby exerting a profound influence on gene regulatory networks. Here we review the components of the IGF-1 signaling pathway that are known targets of miRNA regulation, and highlight recent studies that suggest therapeutic potential of these miRNAs against various diseases.
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Affiliation(s)
- Hwa Jin Jung
- Department of Genetics, Albert Einstein College of Medicine New York, NY, USA
| | - Yousin Suh
- Department of Genetics, Albert Einstein College of Medicine New York, NY, USA ; Department of Medicine, Albert Einstein College of Medicine New York, NY, USA ; Institute for Aging Research, Diabetes Research and Training Center, Albert Einstein College of Medicine New York, NY, USA
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