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Quiring A, Spielmann H, Teping F, Saffour S, Khafaji F, Schulz-Schaeffer W, Monfroy N, Oertel J, Linsler S, Sippl C. Epigenetic Characteristics in Primary and Recurrent Glioblastoma-Influence on the Clinical Course. Biomedicines 2024; 12:2078. [PMID: 39335591 PMCID: PMC11429499 DOI: 10.3390/biomedicines12092078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2024] [Revised: 09/06/2024] [Accepted: 09/08/2024] [Indexed: 09/30/2024] Open
Abstract
OBJECTIVE Epigenetic tumor characteristics are in focus for glioblastoma prognosis. This raises the question if these characteristics present with stable expression during the progression of the disease, and if potential temporal instability might influence their prognostic value. METHODS A total of 44 patients suffering from glioblastoma who were treated for their primary and relapse tumors were included in the study. Tumor specimens from the initial and recurrent tumor resection were subjected to evaluation of MGMT, p15, and p16 methylation statuses. MiRNA-21, -24, -26a, and -181d expression was evaluated as well. The stability of these epigenetic markers during the progression of the disease was correlated with further clinical data. A Cancer Genome Atlas (TCGA) dataset of 224 glioblastoma patients was used as an independent cohort to validate the results. RESULTS Instability was observed in all examined epigenetic markers. MGMT methylation changed in 30% of patients, p15 methylation changed in 35%, and p16 methylation changed in 37.5% of cases. MiRNA expression in corresponding initial and relapse tumor specimens varied considerably in general, individual cases presented with a stable expression. Patients with a decreased expression of miRNA-21 in their recurrence tumor showed significantly longer overall survival. These results are supported by the data from TCGA indicating similar results. CONCLUSIONS Epigenetic characteristics may change during the course of glioblastoma disease. This may influence the prognostic value of derived molecular markers.
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Affiliation(s)
- Alexander Quiring
- Department of Neurosurgery, Klinikum Rechts Der Isar, Technical University Munich School of Medicine, 80333 Munich, Germany
| | - Hannah Spielmann
- Department of Neurosurgery, Faculty of Medicine, Saarland University, 66421 Homburg/Saar, Germany
| | - Fritz Teping
- Department of Neurosurgery, Faculty of Medicine, Saarland University, 66421 Homburg/Saar, Germany
| | - Safwan Saffour
- Department of Neurosurgery, Medical Campus Oberfranken of FAU Erlangen, 91054 Bayreuth, Germany
| | - Fatemeh Khafaji
- Department of Neurosurgery, Medical Campus Oberfranken of FAU Erlangen, 91054 Bayreuth, Germany
| | - Walter Schulz-Schaeffer
- Institute of Neuropathology, Faculty of Medicine, Saarland University, 66421 Homburg/Saar, Germany
| | - Nathan Monfroy
- Department of Neurosurgery, Faculty of Medicine, Saarland University, 66421 Homburg/Saar, Germany
| | - Joachim Oertel
- Department of Neurosurgery, Faculty of Medicine, Saarland University, 66421 Homburg/Saar, Germany
| | - Stefan Linsler
- Department of Neurosurgery, Medical Campus Oberfranken of FAU Erlangen, 91054 Bayreuth, Germany
| | - Christoph Sippl
- Department of Neurosurgery, Medical Campus Oberfranken of FAU Erlangen, 91054 Bayreuth, Germany
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Yao Z, Wu Q, Sheng W, Zhou X, Cheng L, Tian X, Yuan H, Gong L, Wang W, Li B, Peng C. Flavonoidal alkaloids: Emerging targets for drug discovery from Nature's bounty. Fitoterapia 2024; 177:106099. [PMID: 38945491 DOI: 10.1016/j.fitote.2024.106099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 07/02/2024]
Abstract
This paper explores the potential of flavonoid alkaloids, a unique class of compounds that contain both flavonoid and alkaloid structures, as emerging targets for drug discovery. These compounds exhibit diverse biological activities, such as anti-inflammatory, anti-cancer, and anti-diabetic effects, which are attributed to the combination of different flavonoid scaffolds and alkaloid groups. Flavonoid alkaloids have attracted researchers' attention due to their diverse structures and important bio-activities. Therefore, this review summarizes recent advances in the extraction, purification, structural characterization, synthesis pathways and biological activities of flavonoid alkaloids from natural sources. Finally, the potential prospects and challenges associated with this class of compounds in pharmacological research are discussed along with details of a mechanistic investigation and future clinical applications in this research field.
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Affiliation(s)
- Zhijian Yao
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Hunan Provincial TCM and Ethnomedicine Internationnal Science & Technology Innovation Cooperation Base, Hunan Province Laboratory of Natural Medicial Resources and Functions, Changsha 410208, China
| | - Qian Wu
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Hunan Provincial TCM and Ethnomedicine Internationnal Science & Technology Innovation Cooperation Base, Hunan Province Laboratory of Natural Medicial Resources and Functions, Changsha 410208, China; Chinese Medicine Hospital of Hengyang, Hengyang 421009, China
| | - Wenbing Sheng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Hunan Provincial TCM and Ethnomedicine Internationnal Science & Technology Innovation Cooperation Base, Hunan Province Laboratory of Natural Medicial Resources and Functions, Changsha 410208, China
| | - XuDong Zhou
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Hunan Provincial TCM and Ethnomedicine Internationnal Science & Technology Innovation Cooperation Base, Hunan Province Laboratory of Natural Medicial Resources and Functions, Changsha 410208, China
| | - Lidong Cheng
- Shimen Yirentang Traditional Chinese Medicine Sliced Medicine Co., Ltd. Changde 415300, China
| | - Xing Tian
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Hunan Provincial TCM and Ethnomedicine Internationnal Science & Technology Innovation Cooperation Base, Hunan Province Laboratory of Natural Medicial Resources and Functions, Changsha 410208, China
| | - Hanwen Yuan
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Hunan Provincial TCM and Ethnomedicine Internationnal Science & Technology Innovation Cooperation Base, Hunan Province Laboratory of Natural Medicial Resources and Functions, Changsha 410208, China
| | - Limin Gong
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Hunan Provincial TCM and Ethnomedicine Internationnal Science & Technology Innovation Cooperation Base, Hunan Province Laboratory of Natural Medicial Resources and Functions, Changsha 410208, China
| | - Wei Wang
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Hunan Provincial TCM and Ethnomedicine Internationnal Science & Technology Innovation Cooperation Base, Hunan Province Laboratory of Natural Medicial Resources and Functions, Changsha 410208, China
| | - Bin Li
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Hunan Provincial TCM and Ethnomedicine Internationnal Science & Technology Innovation Cooperation Base, Hunan Province Laboratory of Natural Medicial Resources and Functions, Changsha 410208, China.
| | - Caiyun Peng
- TCM and Ethnomedicine Innovation & Development International Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, Hunan Provincial TCM and Ethnomedicine Internationnal Science & Technology Innovation Cooperation Base, Hunan Province Laboratory of Natural Medicial Resources and Functions, Changsha 410208, China; Science & Technology Innovation Center, Hunan University of Chinese Medicine, Changsha 410208, China.
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Barrios-Palacios D, Organista-Nava J, Balandrán JC, Alarcón-Romero LDC, Zubillaga-Guerrero MI, Illades-Aguiar B, Rivas-Alarcón AA, Diaz-Lucas JJ, Gómez-Gómez Y, Leyva-Vázquez MA. The Role of miRNAs in Childhood Acute Lymphoblastic Leukemia Relapse and the Associated Molecular Mechanisms. Int J Mol Sci 2023; 25:119. [PMID: 38203290 PMCID: PMC10779195 DOI: 10.3390/ijms25010119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/15/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
Acute lymphoblastic leukemia (ALL) is the most common cancer in children worldwide. Although ALL patients' overall survival rates in wealthy countries currently surpass 80%, 15-20% of patients still experience relapse. The underlying mechanisms of relapse are still not fully understood, and little progress has been made in treating refractory or relapsed disease. Disease relapse and treatment failure are common causes of leukemia-related death. In ALL relapse, several gene signatures have been identified, but it is also important to study miRNAs involved in ALL relapse in an effort to avoid relapse and to achieve better survival rates since miRNAs regulate target genes that participate in signaling pathways involved in relapse, such as those related to drug resistance, survival signals, and antiapoptotic mechanisms. Several miRNAs, such as miR-24, miR-27a, miR-99/100, miR-124, miR-1225b, miR-128b, miR-142-3p, miR-155 and miR-335-3p, are valuable biomarkers for prognosis and treatment response in ALL patients. Thus, this review aimed to analyze the primary miRNAs involved in pediatric ALL relapse and explore the underlying molecular mechanisms in an effort to identify miRNAs that may be potential candidates for anti-ALL therapy soon.
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Affiliation(s)
- Dalia Barrios-Palacios
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Guerrero, Mexico; (D.B.-P.); (J.O.-N.); (B.I.-A.); (A.A.R.-A.); (J.J.D.-L.)
| | - Jorge Organista-Nava
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Guerrero, Mexico; (D.B.-P.); (J.O.-N.); (B.I.-A.); (A.A.R.-A.); (J.J.D.-L.)
| | - Juan Carlos Balandrán
- Department of Pathology and Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA;
| | - Luz del Carmen Alarcón-Romero
- Laboratorio de Citopatología, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Guerrero, Mexico; (L.d.C.A.-R.); (M.I.Z.-G.)
| | - Ma Isabel Zubillaga-Guerrero
- Laboratorio de Citopatología, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Guerrero, Mexico; (L.d.C.A.-R.); (M.I.Z.-G.)
| | - Berenice Illades-Aguiar
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Guerrero, Mexico; (D.B.-P.); (J.O.-N.); (B.I.-A.); (A.A.R.-A.); (J.J.D.-L.)
| | - Alinne Ayulieth Rivas-Alarcón
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Guerrero, Mexico; (D.B.-P.); (J.O.-N.); (B.I.-A.); (A.A.R.-A.); (J.J.D.-L.)
| | - Jessica Julieth Diaz-Lucas
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Guerrero, Mexico; (D.B.-P.); (J.O.-N.); (B.I.-A.); (A.A.R.-A.); (J.J.D.-L.)
| | - Yazmín Gómez-Gómez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Guerrero, Mexico; (D.B.-P.); (J.O.-N.); (B.I.-A.); (A.A.R.-A.); (J.J.D.-L.)
| | - Marco Antonio Leyva-Vázquez
- Laboratorio de Biomedicina Molecular, Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Guerrero, Chilpancingo 39090, Guerrero, Mexico; (D.B.-P.); (J.O.-N.); (B.I.-A.); (A.A.R.-A.); (J.J.D.-L.)
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Mamalo AS, Alivirdiloo V, Sadeghnejad A, Hajiabbasi M, Gargari MK, Valilo M. Potential roles of the exosome/microRNA axis in breast cancer. Pathol Res Pract 2023; 251:154845. [PMID: 37839359 DOI: 10.1016/j.prp.2023.154845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 09/19/2023] [Accepted: 10/02/2023] [Indexed: 10/17/2023]
Abstract
Cancer is one of the most common diseases in the world, and various genetic and environmental factors play a key role in its development. Breast cancer is one of the most common and deadly cancers in women. Exosomes are extracellular vesicles (EVs) with an average size of about 100 nm that contain lipids, proteins, microRNAs (miRNAs), and genetic factors and play a significant role in cell signaling, communication, tumorigenesis, and drug resistance. miRNAs are RNAs with about 22 nucleotides, which are synthesized by RNA polymerase and are involved in regulating gene expression, as well as the prevention or progression of cancer. Many studies have indicated the connection between miRNAs and exosomes. According to their findings, it seems that circulating exosomal miRNAs have not been well evaluated as biomarkers for breast cancer diagnosis or monitoring. Therefore, given the importance of miRNAs in exosomes, the goal of the present study was to clarify the relationship between miRNAs in exosomes and the role they play as biomarkers in breast cancer.
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Affiliation(s)
| | - Vahid Alivirdiloo
- Medical Doctor Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran
| | - Azadeh Sadeghnejad
- Department of Animal Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | | | - Morad Kohandel Gargari
- Imamreza Hospital, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Valilo
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran; Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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Hu Q, Huang T. Regulation of the Cell Cycle by ncRNAs Affects the Efficiency of CDK4/6 Inhibition. Int J Mol Sci 2023; 24:ijms24108939. [PMID: 37240281 DOI: 10.3390/ijms24108939] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Cyclin-dependent kinases (CDKs) regulate cell division at multiple levels. Aberrant proliferation induced by abnormal cell cycle is a hallmark of cancer. Over the past few decades, several drugs that inhibit CDK activity have been created to stop the development of cancer cells. The third generation of selective CDK4/6 inhibition has proceeded into clinical trials for a range of cancers and is quickly becoming the backbone of contemporary cancer therapy. Non-coding RNAs, or ncRNAs, do not encode proteins. Many studies have demonstrated the involvement of ncRNAs in the regulation of the cell cycle and their abnormal expression in cancer. By interacting with important cell cycle regulators, preclinical studies have demonstrated that ncRNAs may decrease or increase the treatment outcome of CDK4/6 inhibition. As a result, cell cycle-associated ncRNAs may act as predictors of CDK4/6 inhibition efficacy and perhaps present novel candidates for tumor therapy and diagnosis.
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Affiliation(s)
- Qingyi Hu
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Tao Huang
- Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Christoph S, Alicia S, Fritz T, Vanessa T, Ralf K, Jin KY, Stefan L, Joachim O. The intra-tumoral heterogeneity in glioblastoma - a limitation for prognostic value of epigenetic markers? Acta Neurochir (Wien) 2023; 165:1635-1644. [PMID: 37083881 DOI: 10.1007/s00701-023-05594-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 04/10/2023] [Indexed: 04/22/2023]
Abstract
OBJECTIVE Epigenetic tumor features are getting into focus as prognostic markers in glioblastoma. Whether intra-tumoral heterogeneity in these epigenetic characteristics may influence prognostic value remains unclear. METHODS Of 154 patients suffering from glioblastoma, 120 patients served as reference collective, while 34 patients were compiled as test collective. MGMT, p15, and p16 promoter methylation and miRNA expression levels (miRNA-21, miRNA-24, miRNA-26a, and miRNA-181d) were measured in each tumor specimen. Serving as a statistical baseline, epigenetic heterogeneity between tumors (inter-tumoral) was estimated within a triplet of three tumor specimens from three different reference patients. For estimation of epigenetic heterogeneity within a tumor (intra-tumoral), previous results were compared to three tumor specimens within one glioblastoma of patients of the test collective. Resulting levels of heterogeneity were then correlated with survival and validated by an external TCGA data set. RESULTS Heterogeneity in MGMT promoter methylation occurred less likely in the test group compared to the reference group. No difference in heterogeneity was observed between test and reference group regarding p15 and p16 methylation. Intra-tumoral heterogeneity within the test group regarding miRNA-21, miRNA-24, miRNA-26a, and miRNA-181d expression was not distinguishable from inter-tumoral heterogeneity. A homogenously increased miRNA-21 expression was associated with reduced overall survival in the test collective. The findings could be validated by comparison with TCGA datasets. CONCLUSION Heterogeneity of epigenetic characteristics in one glioblastoma may be of the same magnitude as heterogeneity between different patients. Not only the extent of epigenetic characteristics but also the extent of intra-tumoral heterogeneity may influence survival in glioblastoma.
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Affiliation(s)
- Sippl Christoph
- Department of Neurosurgery, Faculty of Medicine, University of Saarland, Homburg/Saar, Germany.
| | - Saenz Alicia
- Department of Neurosurgery, Faculty of Medicine, University of Saarland, Homburg/Saar, Germany
| | - Teping Fritz
- Department of Neurosurgery, Faculty of Medicine, University of Saarland, Homburg/Saar, Germany
| | - Trenkpohl Vanessa
- Department of Neurosurgery, Faculty of Medicine, University of Saarland, Homburg/Saar, Germany
| | - Ketter Ralf
- Department of Neurosurgery, Faculty of Medicine, University of Saarland, Homburg/Saar, Germany
| | - Kim Yoo Jin
- Institute of Pathology, Faculty of Medicine, University of Saarland, Glockenstraße 54, Kaiserslautern, Germany
| | - Linsler Stefan
- Department of Neurosurgery, Faculty of Medicine, University of Saarland, Homburg/Saar, Germany
| | - Oertel Joachim
- Department of Neurosurgery, Faculty of Medicine, University of Saarland, Homburg/Saar, Germany
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Si Z, Zhong Y, Lao S, Wu Y, Zhong G, Zeng W. The Role of miRNAs in the Resistance of Anthracyclines in Breast Cancer: A Systematic Review. Front Oncol 2022; 12:899145. [PMID: 35664800 PMCID: PMC9157424 DOI: 10.3389/fonc.2022.899145] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 04/13/2022] [Indexed: 11/13/2022] Open
Abstract
Breast cancer has been reported as the most common cancer in women globally, with 2.26 million new cases in 2020. While anthracyclines are the first-line drug for breast cancer, they cause a variety of adverse reactions and drug resistance, especially for triple-negative breast cancer, which can lead to poor prognosis, high relapse, and mortality rate. MicroRNAs (miRNAs) have been shown to be important in the initiation, development and metastasis of malignancies and their abnormal transcription levels may influence the efficacy of anthracyclines by participating in the pathologic mechanisms of breast cancer. Therefore, it is essential to understand the exact role of miRNAs in the treatment of breast cancer with anthracyclines. In this review, we outline the mechanisms and signaling pathways involved in miRNAs in the treatment of breast cancer using anthracyclines. The role of miRNA in the diagnosis, prognosis and treatment of breast cancer patients is discussed, along with the involvement of miRNAs in chemotherapy for breast cancer.
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Affiliation(s)
- Zihan Si
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, China
| | - Yan Zhong
- Shenzhen Baoan Women’s and Children’s Hospital, Jinan University, Shenzhen, China
| | - Sixian Lao
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, China
| | - Yufeng Wu
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, China
| | - Guoping Zhong
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, China
| | - Weiwei Zeng
- The Second People's Hospital of Longgang District, Shenzhen, China
- Shenzhen Baoan Women’s and Children’s Hospital, Jinan University, Shenzhen, China
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Bencivenga D, Stampone E, Vastante A, Barahmeh M, Della Ragione F, Borriello A. An Unanticipated Modulation of Cyclin-Dependent Kinase Inhibitors: The Role of Long Non-Coding RNAs. Cells 2022; 11:cells11081346. [PMID: 35456025 PMCID: PMC9028986 DOI: 10.3390/cells11081346] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/08/2022] [Accepted: 04/11/2022] [Indexed: 12/13/2022] Open
Abstract
It is now definitively established that a large part of the human genome is transcribed. However, only a scarce percentage of the transcriptome (about 1.2%) consists of RNAs that are translated into proteins, while the large majority of transcripts include a variety of RNA families with different dimensions and functions. Within this heterogeneous RNA world, a significant fraction consists of sequences with a length of more than 200 bases that form the so-called long non-coding RNA family. The functions of long non-coding RNAs range from the regulation of gene transcription to the changes in DNA topology and nucleosome modification and structural organization, to paraspeckle formation and cellular organelles maturation. This review is focused on the role of long non-coding RNAs as regulators of cyclin-dependent kinase inhibitors’ (CDKIs) levels and activities. Cyclin-dependent kinases are enzymes necessary for the tuned progression of the cell division cycle. The control of their activity takes place at various levels. Among these, interaction with CDKIs is a vital mechanism. Through CDKI modulation, long non-coding RNAs implement control over cellular physiology and are associated with numerous pathologies. However, although there are robust data in the literature, the role of long non-coding RNAs in the modulation of CDKIs appears to still be underestimated, as well as their importance in cell proliferation control.
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Wurtzel JGT, Lazar S, Sikder S, Cai KQ, Astsaturov I, Weyrich AS, Rowley JW, Goldfinger LE. Platelet microRNAs inhibit primary tumor growth via broad modulation of tumor cell mRNA expression in ectopic pancreatic cancer in mice. PLoS One 2021; 16:e0261633. [PMID: 34936674 PMCID: PMC8694476 DOI: 10.1371/journal.pone.0261633] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 12/06/2021] [Indexed: 11/19/2022] Open
Abstract
We investigated the contributions of platelet microRNAs (miRNAs) to the rate of growth and regulation of gene expression in primary ectopic tumors using mouse models. We previously identified an inhibitory role for platelets in solid tumor growth, mediated by tumor infiltration of platelet microvesicles (microparticles) which are enriched in platelet-derived miRNAs. To investigate the specific roles of platelet miRNAs in tumor growth models, we implanted pancreatic ductal adenocarcinoma cells as a bolus into mice with megakaryocyte-/platelet-specific depletion of mature miRNAs. We observed an ~50% increase in the rate of growth of ectopic primary tumors in these mice compared to controls including at early stages, associated with reduced apoptosis in the tumors, in particular in tumor cells associated with platelet microvesicles-which were depleted of platelet-enriched miRNAs-demonstrating a specific role for platelet miRNAs in modulation of primary tumor growth. Differential expression RNA sequencing of tumor cells isolated from advanced primary tumors revealed a broad cohort of mRNAs modulated in the tumor cells as a function of host platelet miRNAs. Altered genes comprised 548 up-regulated transcripts and 43 down-regulated transcripts, mostly mRNAs altogether spanning a variety of growth signaling pathways-notably pathways related to epithelial-mesenchymal transition-in tumor cells from platelet miRNA-deleted mice compared with those from control mice. Tumors in platelet miRNA-depleted mice showed more sarcomatoid growth and more advanced tumor grade, indicating roles for host platelet miRNAs in tumor plasticity. We further validated increased protein expression of selected genes associated with increased cognate mRNAs in the tumors due to platelet miRNA depletion in the host animals, providing proof of principle of widespread effects of platelet miRNAs on tumor cell functional gene expression in primary tumors in vivo. Together, these data demonstrate that platelet-derived miRNAs modulate solid tumor growth in vivo by broad-spectrum restructuring of the tumor cell transcriptome.
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Affiliation(s)
- Jeremy G. T. Wurtzel
- Division of Hematology, Department of Medicine, Cardeza Center for Hemostasis, Thrombosis, and Vascular Biology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States of America
| | - Sophia Lazar
- Division of Hematology, Department of Medicine, Cardeza Center for Hemostasis, Thrombosis, and Vascular Biology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States of America
| | - Sonali Sikder
- Molecular Therapeutics Program and The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, United States of America
| | - Kathy Q. Cai
- Cancer Biology Program and Histopathology Facility, Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA, United States of America
| | - Igor Astsaturov
- Molecular Therapeutics Program and The Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, United States of America
| | - Andrew S. Weyrich
- Molecular Medicine Program, Pathology Division, Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States of America
| | - Jesse W. Rowley
- Molecular Medicine Program, Pulmonary Division, Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States of America
| | - Lawrence E. Goldfinger
- Division of Hematology, Department of Medicine, Cardeza Center for Hemostasis, Thrombosis, and Vascular Biology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States of America
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Dong F, Pu Y, Lv Y, Liu X, Cao Y. Protective effect of Pulsatilla saponin A on acute myocardial infarction via miR-24-3p/p16. Toxicol Mech Methods 2021; 32:27-36. [PMID: 34412561 DOI: 10.1080/15376516.2021.1963364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
The effect of Pulsatilla saponin A (PsA) on acute myocardial infarction (AMI) was unknown. This study targeted to examine the roles of PsA on hypoxia-triggered toxicity to H9c2 cells and reveal the potential mechanism. H9c2 cells were maintained under a hypoxic environment for 12 h to construct the AMI cell model and the cells were pretreated by PsA. Hypoxia triggered toxicity to H9c2 cells and the anti-toxicity effect of PsA was evaluated by CCK8, TUNEL, and Western blot. The levels of miR-24-3p and p16 in H9c2 cells, AMI group tissues, and their respective controls were assessed using qRT-PCR. The dual-luciferase assay was applied to verify the targeting mechanism of miR-24-3p on p16. Then the effects of miR-24-3p inhibitor or/and si-p16 on H9c2 cells treated with PsA under hypoxia were detected by CCK8, TUNEL, and Western blot. Flow cytometry was executed to determine the cell cycle. Hypoxia decreased viability and proliferation and increased apoptosis of H9c2 cells, which were ameliorated by PsA pretreatment. The level of miR-24-3p was diminished, but p16 expression was elevated in hypoxia-treated cells and AMI group tissues. MiR-24-3p could sponge p16 in hypoxia-treated cells. Furthermore, the impact of applying miR-24-3p inhibitor on PsA and hypoxia-treated cells could be reversed by si-p16. PsA relieved hypoxia-triggered cell toxicity via miR-24-3p/p16 axis. These findings provided some fresh insights into the potential therapeutic effects of the application of PsA in AMI.
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Affiliation(s)
- Feng Dong
- Department of General Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan City, China
| | - Yanhua Pu
- Department of General Family Medicine No.1, The Fourth Hospital of Jinan, Jinan City, China
| | - Yanfei Lv
- Department of Rehabilitation Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan City, China
| | - Xiujuan Liu
- Department of Cardiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan City, China
| | - Yimin Cao
- Department of Emergency, Jinan Traditional Chinese Medicine Hospital, Jinan City, China
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11
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Hussein NA, Malla S, Pasternak MA, Terrero D, Brown NG, Ashby CR, Assaraf YG, Chen ZS, Tiwari AK. The role of endolysosomal trafficking in anticancer drug resistance. Drug Resist Updat 2021; 57:100769. [PMID: 34217999 DOI: 10.1016/j.drup.2021.100769] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 04/10/2021] [Accepted: 05/14/2021] [Indexed: 02/08/2023]
Abstract
Multidrug resistance (MDR) remains a major obstacle towards curative treatment of cancer. Despite considerable progress in delineating the basis of intrinsic and acquired MDR, the underlying molecular mechanisms remain to be elucidated. Emerging evidences suggest that dysregulation in endolysosomal compartments is involved in mediating MDR through multiple mechanisms, such as alterations in endosomes, lysosomes and autophagosomes, that traffic and biodegrade the molecular cargo through macropinocytosis, autophagy and endocytosis. For example, altered lysosomal pH, in combination with transcription factor EB (TFEB)-mediated lysosomal biogenesis, increases the sequestration of hydrophobic anti-cancer drugs that are weak bases, thereby producing an insufficient and off-target accumulation of anti-cancer drugs in MDR cancer cells. Thus, the use of well-tolerated, alkalinizing compounds that selectively block Vacuolar H⁺-ATPase (V-ATPase) may be an important strategy to overcome MDR in cancer cells and increase chemotherapeutic efficacy. Other mechanisms of endolysosomal-mediated drug resistance include increases in the expression of lysosomal proteases and cathepsins that are involved in mediating carcinogenesis and chemoresistance. Therefore, blocking the trafficking and maturation of lysosomal proteases or direct inhibition of cathepsin activity in the cytosol may represent novel therapeutic modalities to overcome MDR. Furthermore, endolysosomal compartments involved in catabolic pathways, such as macropinocytosis and autophagy, are also shown to be involved in the development of MDR. Here, we review the role of endolysosomal trafficking in MDR development and discuss how targeting endolysosomal pathways could emerge as a new therapeutic strategy to overcome chemoresistance in cancer.
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Affiliation(s)
- Noor A Hussein
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, 43614, OH, USA
| | - Saloni Malla
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, 43614, OH, USA
| | - Mariah A Pasternak
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, 43614, OH, USA
| | - David Terrero
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, 43614, OH, USA
| | - Noah G Brown
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, 43614, OH, USA
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy & Pharmaceutical Sciences, St. John's University, Queens, NY, USA
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy & Pharmaceutical Sciences, St. John's University, Queens, NY, USA.
| | - Amit K Tiwari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy & Pharmaceutical Sciences, University of Toledo, Toledo, 43614, OH, USA; Department of Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, 43614, OH, USA.
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12
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Potter ML, Hill WD, Isales CM, Hamrick MW, Fulzele S. MicroRNAs are critical regulators of senescence and aging in mesenchymal stem cells. Bone 2021; 142:115679. [PMID: 33022453 PMCID: PMC7901145 DOI: 10.1016/j.bone.2020.115679] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 07/16/2020] [Accepted: 07/28/2020] [Indexed: 01/10/2023]
Abstract
MicroRNAs (miRNAs) have recently come under scrutiny for their role in various age-related diseases. Similarly, cellular senescence has been linked to disease and aging. MicroRNAs and senescence likely play an intertwined role in driving these pathologic states. In this review, we present the connection between these two drivers of age-related disease concerning mesenchymal stem cells (MSCs). First, we summarize key miRNAs that are differentially expressed in MSCs and other musculoskeletal lineage cells during senescence and aging. Additionally, we also reviewed miRNAs that are regulated via traditional senescence-associated secretory phenotype (SASP) cytokines in MSC. Lastly, we summarize miRNAs that have been found to target components of the cell cycle arrest pathways inherently activated in senescence. This review attempts to highlight potential miRNA targets for regenerative medicine applications in age-related musculoskeletal disease.
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Affiliation(s)
- Matthew L Potter
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America
| | - William D Hill
- Medical University of South Carolina, Charleston, SC 29403, United States of America; Ralph H Johnson Veterans Affairs Medical Center, Charleston, SC, 29403, United States of America
| | - Carlos M Isales
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America; Department of Medicine, Augusta University, Augusta, GA, United States of America; Institute of Healthy Aging, Augusta University, Augusta, GA, United States of America
| | - Mark W Hamrick
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America; Institute of Healthy Aging, Augusta University, Augusta, GA, United States of America; Department of Cell Biology and Anatomy, Augusta University, Augusta, GA, United States of America
| | - Sadanand Fulzele
- Department of Orthopedics, Augusta University, Augusta, GA, United States of America; Department of Medicine, Augusta University, Augusta, GA, United States of America; Institute of Healthy Aging, Augusta University, Augusta, GA, United States of America; Department of Cell Biology and Anatomy, Augusta University, Augusta, GA, United States of America.
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13
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Li X, Tang Y, Jia Z, Zhao X, Chen M. Decreased expression of miR-24 in peripheral plasma of type 2 diabetes mellitus patients associated with diabetic foot ulcer. Wound Repair Regen 2020; 28:728-738. [PMID: 32710681 DOI: 10.1111/wrr.12850] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 06/19/2020] [Accepted: 07/15/2020] [Indexed: 12/15/2022]
Abstract
To examine the correlations of miR-24 expression in peripheral plasma with the onset of diabetic foot ulcer (DFU) and diabetic foot osteomyelitis (DFO) in type 2 diabetes mellitus (T2DM) patients and explore the clinical value of miR-24 as a potential biomarker for the diagnosis and treatment outcomes of DFU and DFO, a total of 60 newly diagnosed T2DM patients without DFU (T2DM group), 112 T2DM patients with DFU (DFU group), and 60 healthy controls (NC group) were included. DFU group were further divided into DFO group (n = 64) and non-DFO group (n = 48). MiR-24 levels were determined by quantitative real-time PCR, while clinical features and risk factors of DFU and DFO were explored. The expression level of miR-24 in T2DM and DFU group was significantly lower than in NC group (P < .05), and that in DFU group was significantly lower than in T2DM group (P < .01). Additionally, the level of miR-24 significantly decreased in DFO group compared to non-DFO group (P < .01). Moreover, it was negatively correlated with the amputation rate in DFU group (P = .043) and positively correlated with healing rate after 8 weeks (P = .036). The multivariate logistic regression analysis confirmed that a low expression of miR-24 was an independent risk factor for DFU and DFO. The ROC curve analysis indicated that the AUC of miR-24 for the diagnosis of DFU and DFO was 0.849 (95% CI, 0.618-0.879, P < .001) and 0.782 (95% CI, 0.595-0.813, P < .001). Thus, a decreased expression of miR-24 of T2DM patients was closely related to the occurrence, development and prognosis of DFU and DFO, suggesting the use of miR-24 as a potential biomarker for the prediction of DFU and DFO.
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Affiliation(s)
- Xueting Li
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Ying Tang
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Zeguo Jia
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Xiaotong Zhao
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China
| | - Mingwei Chen
- Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, Hefei, PR China.,Institute of Traditional Chinese Medicine for the Prevention and Control of Diabetes, Anhui Academy of Chinese Medicine, Hefei, PR China
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14
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Sippl C, Teping F, Ketter R, Braun L, Tremmel L, Schulz-Schaeffer W, Oertel J, Urbschat S. The Influence of Distinct Regulatory miRNAs of the p15/p16/RB1/E2F Pathway on the Clinical Progression of Glioblastoma Multiforme. World Neurosurg 2019; 132:e900-e908. [DOI: 10.1016/j.wneu.2019.07.134] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 07/16/2019] [Accepted: 07/17/2019] [Indexed: 12/15/2022]
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15
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MicroRNA expression profiling analysis in serum for nasopharyngeal carcinoma diagnosis. Gene 2019; 727:144243. [PMID: 31743768 DOI: 10.1016/j.gene.2019.144243] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2019] [Revised: 10/26/2019] [Accepted: 10/29/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Circulating microRNAs have become reliable sources of non-invasive biomarkers for cancer diagnosis. miRNA expression analysis in blood circulation for the identification of novel signatures might assist the early detection of nasopharyngeal carcinoma (NPC) patients. METHODS In the screening stage, the Exiqon miRNA qPCR panel was applied for the selection of candidate miRNAs. Serum samples taken from 208 NPC patients and 238 healthy donors (as normal controls (NCs)) were assigned to into the following three stages (training (30 NPC VS. 30 NCs), testing (138 NPC VS. 166 NCs) and external validation stage (40 NPC VS. 42 NCs)) for further confirmation of differently expressed miRNAs using qRT-PCR. The identified miRNA signatures were further explored in tissue specimens (48 NPC VS. 32 NCs) and serum-derived exosomes samples (32 NPC VS. 32 NCs). RESULTS Five miRNAs in serum including let-7b-5p, miR-140-3p, miR-192-5p, miR-223-3p and miR-24-3p were found to be significantly up-regulated in NPC patients compared to NCs. The five identified miRNAs were further combined into one panel and the areas under the receiver operating characteristic curve (AUCs) for three independent stages were 0.910 (training), 0.916 (testing) and 0.968 (external validation), respectively. miR-192-5p and miR-24-3p were consistently up-regulated in NPC tissues while let-7b-5p and miR-140-3p were conversely down-regulated. In serum-derived exosomes samples, no expression difference was observed between NPC patients and NCs. CONCLUSION A five-miRNA signature was identified in serum to be potential biomarkers for NPC detection.
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16
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García-Gutiérrez L, Delgado MD, León J. MYC Oncogene Contributions to Release of Cell Cycle Brakes. Genes (Basel) 2019; 10:E244. [PMID: 30909496 PMCID: PMC6470592 DOI: 10.3390/genes10030244] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 03/16/2019] [Accepted: 03/18/2019] [Indexed: 12/12/2022] Open
Abstract
Promotion of the cell cycle is a major oncogenic mechanism of the oncogene c-MYC (MYC). MYC promotes the cell cycle by not only activating or inducing cyclins and CDKs but also through the downregulation or the impairment of the activity of a set of proteins that act as cell-cycle brakes. This review is focused on the role of MYC as a cell-cycle brake releaser i.e., how MYC stimulates the cell cycle mainly through the functional inactivation of cell cycle inhibitors. MYC antagonizes the activities and/or the expression levels of p15, ARF, p21, and p27. The mechanism involved differs for each protein. p15 (encoded by CDKN2B) and p21 (CDKN1A) are repressed by MYC at the transcriptional level. In contrast, MYC activates ARF, which contributes to the apoptosis induced by high MYC levels. At least in some cells types, MYC inhibits the transcription of the p27 gene (CDKN1B) but also enhances p27's degradation through the upregulation of components of ubiquitin ligases complexes. The effect of MYC on cell-cycle brakes also opens the possibility of antitumoral therapies based on synthetic lethal interactions involving MYC and CDKs, for which a series of inhibitors are being developed and tested in clinical trials.
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Affiliation(s)
- Lucía García-Gutiérrez
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC) CSIC-Universidad de Cantabria and Department of Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain.
- Current address: Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
| | - María Dolores Delgado
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC) CSIC-Universidad de Cantabria and Department of Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain.
| | - Javier León
- Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC) CSIC-Universidad de Cantabria and Department of Biología Molecular, Universidad de Cantabria, 39011 Santander, Spain.
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Abstract
Cellular senescence is a state of permanent cell-cycle arrest triggered by different internal and external stimuli. This phenomenon is considered to be both beneficial and detrimental depending on the cell types and biological contexts. During normal embryonic development and after tissue injury, cellular senescence is critical for tissue remodeling. In addition, this process is useful for arresting growth of tumor cells, particularly during early onset of tumorigenesis. However, accumulation of senescent cells decreases tissue regenerative capabilities and induces inflammation, which is responsible for cancer and organismal aging. Therefore cellular senescence has to be tightly regulated, and dysregulation might lead to the aging and human diseases. Among many regulators of cellular senescence, in this review, I will focus on microRNAs, small non-coding RNAs playing critical roles in diverse biological events including cellular senescence. [BMB Reports 2018; 51(10): 494-500].
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Affiliation(s)
- Nayoung Suh
- Department of Pharmaceutical Engineering, Soon Chun Hyang University, Asan 31538, Korea
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18
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Qiaoqiao C, Li H, Liu X, Yan Z, Zhao M, Xu Z, Wang Z, Shi K. MiR-24-3p regulates cell proliferation and milk protein synthesis of mammary epithelial cells through menin in dairy cows. J Cell Physiol 2019; 234:1522-1533. [PMID: 30221364 PMCID: PMC6282567 DOI: 10.1002/jcp.27017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 06/25/2018] [Indexed: 01/04/2023]
Abstract
MiR-24-3p, a broadly conserved, small, noncoding RNA, is abundantly expressed in mammary tissue. However, its regulatory role in this tissue remains poorly understood. It was predicted that miR-24-3p targets the 3' untranslated region (3'-UTR) of multiple endocrine neoplasia type 1 (MEN1), an important regulatory factor in mammary tissue. The objective of this study was to investigate the function of miR-24-3p in mammary cells. Using a luciferase assay in mammary epithelial cells (MAC-T), miR-24-3p was confirmed to target the 3'-UTR of MEN1. Furthermore, miR-24-3p negatively regulated the expression of the MEN1 gene and its encoded protein, menin. miR-24-3p enhanced proliferation of MAC-T by promoting G1/S phase progression. MiR-24-3p also regulated the expression of key factors involved in phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin and Janus kinase/signal transducer and activators of transcription signaling pathways, therefore controlling milk protein synthesis in epithelial cells. Thus, miR-24-3p appears to act on MAC-T by targeting MEN1. The expression of miR-24-3p was controlled by MEN1/menin, indicating a negative feedback loop between miR-24-3p and MEN1/menin. The negatively inhibited expression pattern of miR-24-3p and MEN1 was active in mammary tissues at different lactation stages. The feedback mechanism is a new concept to further understand the lactation cycle of mammary glands and can possibly to be manipulated to improve milk yield and quality.
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Affiliation(s)
- Cao Qiaoqiao
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural UniversityTai’anShandongChina
| | - Honghui Li
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural UniversityTai’anShandongChina
| | - Xue Liu
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural UniversityTai’anShandongChina
| | - Zhengui Yan
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural UniversityTai’anShandongChina
| | - Meng Zhao
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural UniversityTai’anShandongChina
| | - Zhongjin Xu
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural UniversityTai’anShandongChina
| | - Zhonghua Wang
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural UniversityTai’anShandongChina
| | - Kerong Shi
- Shandong Key Laboratory of Animal Bioengineering and Disease Prevention, College of Animal Science and Technology, Shandong Agricultural UniversityTai’anShandongChina
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19
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Changjun L, Feizhou H, Dezhen P, Zhao L, Xianhai M. MiR-545-3p/MT1M axis regulates cell proliferation, invasion and migration in hepatocellular carcinoma. Biomed Pharmacother 2018; 108:347-354. [PMID: 30227328 DOI: 10.1016/j.biopha.2018.09.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 09/02/2018] [Accepted: 09/03/2018] [Indexed: 12/16/2022] Open
Abstract
Studies have shown that metallothionein 1 M (MT1M) is a tumor suppressor gene which is frequently down-regulated in human hepatocellular carcinoma (HCC). The methylation of MT1M promoter region is one of the important transcriptional regulation mechanisms that contribute to the loss of its expression. In our study, we found that there are still half of the 55 HCC tumor tissues in our cohort do not share the promoter methylation of MT1M. So, we speculated there maybe another mechanism participating in the downregulation of MT1M in HCC. Then, we provided evidences that miR-545-3p, which served as a tumor promoter, post-transcriptionally regulate MT1M in HCC through binding to its untranslated region (3'UTR). Taking together, we investigated the role of miR-545-3p in the process of HCC through regulating MT1M.
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Affiliation(s)
- Liu Changjun
- Department of Hepatobiliary Surgery, Hunan People's Hospital, Changsha 410005, China; Department of General surgery, the Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Huang Feizhou
- Department of General surgery, the Third Xiangya Hospital of Central South University, Changsha 410013, China.
| | - Peng Dezhen
- Department of Medicine-Neurology, the Second Xiangya Hospital of Central South University, Changsha 410011, China
| | - Lei Zhao
- Department of Hepatobiliary Surgery, Hunan People's Hospital, Changsha 410005, China
| | - Mao Xianhai
- Department of Hepatobiliary Surgery, Hunan People's Hospital, Changsha 410005, China
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20
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Yu B, Gao W, Zhou H, Miao X, Chang Y, Wang L, Xu M, Ni G. Propofol induces apoptosis of breast cancer cells by downregulation of miR-24 signal pathway. Cancer Biomark 2018; 21:513-519. [PMID: 29103019 DOI: 10.3233/cbm-170234] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND OBJECTIVE Propofol, an intravenous anesthetic agent, has been found to inhibit growth of breast cancer cells. However, the mechanisms underlying the antitumor are not known. A recent report has found that propofol could significantly downregulate miR-24 expression in the human malignant cancers. In breast cancer cells, overexpression of miR-24 promotes cell proliferation and inhibits cell apoptosis by downregulation of p27. The miR-24 has been reported to be overexpressed in breast cancer and breast cancer cell lines. In the present study, we hypothesized that propofol induces apoptosis of breast cancer cells by miR-24/p27 signal pathway. METHODS Breast cancer MDA-MB-435 cells were exposed to propofol (10 μM) for 6 hr and cell death was assessed using TUNEL staining, Flow cytometry and cleaved caspase-3 expression. microRNA-24 (miR-24) expression was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR). miR-24 was overexpressed using a miR-24 mimic. P27 was knocked down using a small interfering RNA. p27 and cleaved caspase-3 expression was assessed by Western blot. RESULTS MDA-MB-435 exposed to propofol showed a significant increase in apoptotic cells, followed by the downregulation of miR-24, upregulation of p27 expression and cleaved caspase-3 expression. Targeting p27 inhibits propofol-induced cell apoptosis; miR-24 overexpression decreased propofol-induced cell apoptosis, cleaved caspase-3 and p27 expression. CONCLUSIONS Propofol inducescell death in MDA-MB-435 cells via inactivation of miR-24/p27 signal pathway.
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Affiliation(s)
- Benxia Yu
- Department of Imaging, Yantai Yuhuangding Hospital, Yantai, Shandong, China.,Department of Imaging, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Wei Gao
- Department of Imaging, Yantai Yuhuangding Hospital, Yantai, Shandong, China.,Department of Imaging, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Hui Zhou
- Department of Anesthesiology, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Xia Miao
- Department of Clinical Laboratory, The Affiliated Hospital of Weifang Medical College, Weifang, Shandong, China
| | - Yuan Chang
- Department of Anesthesiology, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Liping Wang
- Department of Imaging, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Miao Xu
- Department of Clinical Laboratory, The Affiliated Hospital of Weifang Medical College, Weifang, Shandong, China
| | - Guangzhen Ni
- Department of Clinical Laboratory, The Affiliated Hospital of Weifang Medical College, Weifang, Shandong, China
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21
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Vittoria MA, Shenk EM, O'Rourke KP, Bolgioni AF, Lim S, Kacprzak V, Quinton RJ, Ganem NJ. A genome-wide microRNA screen identifies regulators of tetraploid cell proliferation. Mol Biol Cell 2018; 29:1682-1692. [PMID: 29791254 PMCID: PMC6080710 DOI: 10.1091/mbc.e18-02-0141] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Tetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that ∼40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, nontransformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these antiproliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive gain-of-function genome-wide screen to identify microRNAs (miRNAs) that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g., miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g., miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via down-regulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.
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Affiliation(s)
- Marc A Vittoria
- Department of Pharmacology and Experimental Therapeutics, University School of Medicine, Boston, MA 02118
| | - Elizabeth M Shenk
- Department of Pharmacology and Experimental Therapeutics, University School of Medicine, Boston, MA 02118.,Department of Biomedical Engineering, Boston University, Boston, MA 02118
| | - Kevin P O'Rourke
- Weill Cornell Medicine/Rockefeller University/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10065
| | - Amanda F Bolgioni
- Department of Pharmacology and Experimental Therapeutics, University School of Medicine, Boston, MA 02118
| | - Sanghee Lim
- Department of Pharmacology and Experimental Therapeutics, University School of Medicine, Boston, MA 02118
| | - Victoria Kacprzak
- Department of Pharmacology and Experimental Therapeutics, University School of Medicine, Boston, MA 02118
| | - Ryan J Quinton
- Department of Pharmacology and Experimental Therapeutics, University School of Medicine, Boston, MA 02118
| | - Neil J Ganem
- Department of Pharmacology and Experimental Therapeutics, University School of Medicine, Boston, MA 02118.,Division of Hematology and Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118
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Yin Y, Zhong J, Li SW, Li JZ, Zhou M, Chen Y, Sang Y, Liu L. TRIM11, a direct target of miR-24-3p, promotes cell proliferation and inhibits apoptosis in colon cancer. Oncotarget 2018; 7:86755-86765. [PMID: 27888625 PMCID: PMC5349951 DOI: 10.18632/oncotarget.13550] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 11/07/2016] [Indexed: 12/16/2022] Open
Abstract
TRIM11 (tripartite motif-containing protein 11) is an E3 ubiquitin ligase recently identified as an oncogene in malignant glioma and lung cancer. In the present study, we report that expression of TRIM11 was increased in colon cancer (CC) tissue relative to paired normal tissues and that higher TRIM11 levels predicted poor overall survival (OS) and disease-free survival (DFS) in CC patients. Mechanistically, we showed that miR-24-3p downregulation contributes to TRIM11 upregulation in CC. We also demonstrated that TRIM11 overexpression promotes cell proliferation and colony formation and inhibits apoptosis in CC, while knocking down TRIM11 using CRISPR/Cas9-mediated genome editing inhibited cell proliferation and induced apoptosis. Silencing TRIM11 in vivo decreased tumor growth. These findings indicate that TRIM11 facilitates CC progression by promoting cell proliferation and inhibiting apoptosis and that the novel miR-24-3p/TRIM11 axis may be a useful new target for treating patients with CC.
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Affiliation(s)
- Yan Yin
- Department of Pharmacy, Jiangxi Cancer Hospital, Nanchang, China
| | - Jun Zhong
- Department of Radiotherapy, Jiangxi Cancer Hospital, Nanchang, China
| | - Si-Wei Li
- Department of Radiation Oncology, The Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Jian-Zhe Li
- Department of Pharmacy, Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning, China
| | - Min Zhou
- Department of Pharmacy, Jiangxi Cancer Hospital, Nanchang, China
| | - Yin Chen
- Department of Pharmacy, Jiangxi Cancer Hospital, Nanchang, China
| | - Yi Sang
- Nanchang Key Laboratory of Cancer Pathogenesis and Translational Research, Center Laboratory, The Third Affiliated Hospital, Nanchang University, Nanchang, China
| | - Lijuan Liu
- Department of Pharmacy, Jiangxi Cancer Hospital, Nanchang, China
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Yan M, Dou T, Lv W, Wang X, Zhao L, Chang X, Zhou Z. Integrated analysis of paraquat-induced microRNAs-mRNAs changes in human neural progenitor cells. Toxicol In Vitro 2017; 44:196-205. [DOI: 10.1016/j.tiv.2017.06.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 03/30/2017] [Accepted: 06/10/2017] [Indexed: 10/19/2022]
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MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism. Virchows Arch 2017; 471:401-411. [PMID: 28597079 DOI: 10.1007/s00428-017-2158-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 04/24/2017] [Accepted: 05/17/2017] [Indexed: 12/31/2022]
Abstract
Inherited, germline mutations of menin-coding MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), while somatic MEN1 mutations are the sole main driver mutations in sporadic primary hyperparathyroidism (PHPT), suggesting that menin deficiency has a central role in the pathogenesis of PHPT. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to investigate both the role of MEN1 mutations and potentially MEN1-targeting miRNAs as the underlying cause of menin deficiency in MEN1-associated and sporadic PHPT tissues. Fifty six PHPT tissues, including 16 MEN1-associated tissues, were evaluated. Diagnosis of MEN1 syndrome was based on identification of germline MEN1 mutations. In silico target prediction was used to identify miRNAs potentially targeting MEN1. Menin expression was determined by immunohistochemistry while expression of miRNAs was analyzed by quantitative real-time PCR. Sporadic PHPT tissues were subjected to somatic MEN1 mutation analysis as well. Lack of nuclear menin was identified in all MEN1-associated and in 28% of sporadic PHPT tissues. Somatic MEN1 mutations were found in 25% of sporadic PHPTs. The sensitivity and specificity of menin immunohistochemistry to detect a MEN1 mutation were 86 and 87%, respectively. Expression levels of hsa-miR-24 and hsa-miR-28 were higher in sporadic compared to MEN1-associated PHPT tissues; however, no difference in miRNA levels occurred between menin-positive and menin-negative PHPT tissues. Menin deficiency is the consequence of a MEN1 mutation in most menin-negative PHPT tissues. Elevated expression of hsa-miR-24 and hsa-miR-28 mark the first epigenetic changes observed between sporadic and MEN1-associated PHPT.
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Platelet microparticles infiltrating solid tumors transfer miRNAs that suppress tumor growth. Blood 2017; 130:567-580. [PMID: 28500171 DOI: 10.1182/blood-2016-11-751099] [Citation(s) in RCA: 185] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 05/08/2017] [Indexed: 12/13/2022] Open
Abstract
Platelet-derived microparticles (PMPs) are associated with enhancement of metastasis and poor cancer outcomes. Circulating PMPs transfer platelet microRNAs (miRNAs) to vascular cells. Solid tumor vasculature is highly permeable, allowing the possibility of PMP-tumor cell interaction. Here, we show that PMPs infiltrate solid tumors in humans and mice and transfer platelet-derived RNA, including miRNAs, to tumor cells in vivo and in vitro, resulting in tumor cell apoptosis. MiR-24 was a major species in this transfer. PMP transfusion inhibited growth of both lung and colon carcinoma ectopic tumors, whereas blockade of miR-24 in tumor cells accelerated tumor growth in vivo, and prevented tumor growth inhibition by PMPs. Conversely, Par4-deleted mice, which had reduced circulating microparticles (MPs), supported accelerated tumor growth which was halted by PMP transfusion. PMP targeting was associated with tumor cell apoptosis in vivo. We identified direct RNA targets of platelet-derived miR-24 in tumor cells, which included mitochondrial mt-Nd2, and Snora75, a noncoding small nucleolar RNA. These RNAs were suppressed in PMP-treated tumor cells, resulting in mitochondrial dysfunction and growth inhibition, in an miR-24-dependent manner. Thus, platelet-derived miRNAs transfer in vivo to tumor cells in solid tumors via infiltrating MPs, regulate tumor cell gene expression, and modulate tumor progression. These findings provide novel insight into mechanisms of horizontal RNA transfer and add multiple layers to the regulatory roles of miRNAs and PMPs in tumor progression. Plasma MP-mediated transfer of regulatory RNAs and modulation of gene expression may be a common feature with important outcomes in contexts of enhanced vascular permeability.
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26
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Munk R, Panda AC, Grammatikakis I, Gorospe M, Abdelmohsen K. Senescence-Associated MicroRNAs. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2017; 334:177-205. [PMID: 28838538 PMCID: PMC8436595 DOI: 10.1016/bs.ircmb.2017.03.008] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Senescent cells arise as a consequence of cellular damage and can have either a detrimental or advantageous impact on tissues and organs depending on the specific cell type and metabolic state. As senescent cells accumulate in tissues with advancing age, they have been implicated in many age-related declines and diseases. The major facets of senescence include two pathways responsible for establishing and maintaining a senescence program, p53/CDKN1A(p21) and CDKN2A(p16)/RB, as well as the senescence-associated secretory phenotype. Numerous MicroRNAs influence senescence by modulating the abundance of key senescence regulatory proteins, generally by lowering the stability and/or translation of mRNAs that encode such factors. Accordingly, understanding the molecular mechanisms by which MicroRNAs influence senescence will enable diagnostic and therapeutic opportunities directed at senescent cells. Here, we review senescence-associated (SA)-MicroRNAs and discuss their implications in senescence-relevant pathologies.
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Affiliation(s)
- Rachel Munk
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Amaresh C Panda
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Ioannis Grammatikakis
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
| | - Kotb Abdelmohsen
- Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.
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Yuan Y, Kluiver J, Koerts J, de Jong D, Rutgers B, Abdul Razak FR, Terpstra M, Plaat BE, Nolte IM, Diepstra A, Visser L, Kok K, van den Berg A. miR-24-3p Is Overexpressed in Hodgkin Lymphoma and Protects Hodgkin and Reed-Sternberg Cells from Apoptosis. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1343-1355. [PMID: 28432871 DOI: 10.1016/j.ajpath.2017.02.016] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 02/16/2017] [Indexed: 12/11/2022]
Abstract
miRNAs play important roles in biological processes, such as proliferation, metabolism, differentiation, and apoptosis, whereas altered expression levels contribute to diseases, such as cancers. We identified miRNAs with aberrant expression in Hodgkin lymphoma (HL) and investigated their role in pathogenesis. Small RNA sequencing revealed 84 significantly differentially expressed miRNAs in HL cell lines as compared to germinal center B cells. Three up-regulated miRNAs-miR-23a-3p, miR-24-3p, and miR-27a-3p-were derived from one primary miRNA transcript. Loss-of-function analyses for these miRNAs and their seed family members resulted in decreased growth on miR-24-3p inhibition in three HL cell lines and of miR-27a/b-3p inhibition in one HL cell line. Apoptosis analysis indicated that the effect of miR-24-3p on cell growth is at least in part caused by an increase of apoptotic cells. Argonaute 2 immunoprecipitation revealed 1142 genes consistently targeted by miRNAs in at least three of four HL cell lines. Furthermore, 52 of the 1142 genes were predicted targets of miR-24-3p. Functional annotation analysis revealed a function related to cell growth, cell death, and/or apoptosis for 15 of the 52 genes. Western blotting of the top five genes showed increased protein levels on miR-24-3p inhibition for CDKN1B/P27kip1 and MYC. In summary, we showed that miR-24-3p is up-regulated in HL and its inhibition impairs cell growth possibly via targeting CDKN1B/P27kip1 and MYC.
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Affiliation(s)
- Ye Yuan
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Institute of Clinical Pharmacology of the Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Joost Kluiver
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jasper Koerts
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Debora de Jong
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Bea Rutgers
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - F Reeny Abdul Razak
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Martijn Terpstra
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Boudewijn E Plaat
- Department of Otorhinolaryngology/Head and Neck Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ilja M Nolte
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Arjan Diepstra
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Lydia Visser
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Klaas Kok
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Anke van den Berg
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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miR clusters target cellular functional complexes by defining their degree of regulatory freedom. Cancer Metastasis Rev 2017; 35:289-322. [PMID: 26970968 DOI: 10.1007/s10555-016-9617-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Using the two paralog miR-23∼27∼24 clusters as an example and combining experimental and clinical data in a systematical approach to microRNA (miR) function and dysregulation, a complex picture of their roles in cancer is drawn. Various findings appear to be contradictory to a larger extent and cannot be fully explained by the classical regulatory network models and feedback loops that are mainly considered by one-to-one regulatory interactions of the involved molecules. Here, we propose an extended model of the regulatory role of miRs that, at least, supplements the usually considered single/oligo-target regulation of certain miRs. The cellular availability of the participating miR members in this model reflects an upper hierarchy level of intracellular and extracellular environmental influences, such as neighboring cells, soluble factors, hypoxia, chemotherapeutic drugs, and irradiation, among others. The novel model is based on the understanding of cellular functional complexes, such as for apoptosis, migration, and proliferation. These complexes consist of many regulatory components that can be targeted by miR cluster members to a different extent but may affect the functional complex in different ways. We propose that the final miR-related effect is a result of the possible degree of regulatory freedom provided by the miR effects on the whole functional complex structure. This degree of regulatory freedom defines to which extent the cellular functional complex can react in response to regulatory triggers, also understood as sensitization (more regulatory response options) or de-sensitization (less regulatory response options) of the system rather than single molecules.
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miR-222 confers the resistance of breast cancer cells to Adriamycin through suppression of p27(kip1) expression. Gene 2016; 590:44-50. [PMID: 27282281 DOI: 10.1016/j.gene.2016.06.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 05/26/2016] [Accepted: 06/04/2016] [Indexed: 01/24/2023]
Abstract
Adriamycin (Adr) is a potent chemotherapeutic agent for chemotherapy of breast cancer patients. Despite impressive initial clinical responses, some developed drug resistance to Adr-based therapy and the mechanisms underlying breast cancer cells resistance to Adr are not well known. In our previous study, in vitro, we verified that miR-222 was upregulated in Adr-resistant breast cancer cells (MCF-7/Adr) compared with the sensitive parental cells (MCF-7/S). Here, miR-222 inhibitors or mimics were transfected into MCF-7 cell lines. RT-qPCR and western blot were used to detect the expression of p27(kip1). Immunofluorescence showed that miR-222 altered the subcellular location of p27(kip1) in nucleus. MTT was employed to verify the sensitivity of breast cancer cell lines to Adr. Flow cytometry showed the apoptosis and cell cycles of the cells after adding Adr. The results showed that downregulation of miR-222 in MCF-7/Adr increased sensitivity to Adr and Adr-induced apoptosis, and arrested the cells in G1 phase, accompanied by more expressions of p27(kip1), especially in nucleus. Furthermore, overexpressed miR-222 in MCF-7/S had the inverse results. Taken together, the results found that miR-222 induced Adr-resistance at least in part via suppressing p27(kip1) expression and altering its subcellular localization, and miR-222 inhibitors could reverse Adr-resistance of breast cancer cells. These results disclosed that the future holds much promise for the targeted therapeutic in the treatment of Adr-resistant breast cancer.
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30
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Lynch SM, McKenna MM, Walsh CP, McKenna DJ. miR-24 regulates CDKN1B/p27 expression in prostate cancer. Prostate 2016; 76:637-48. [PMID: 26847530 DOI: 10.1002/pros.23156] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Accepted: 01/08/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs) are small, non-coding RNA molecules with an important role in cancer. In prostate cancer, several miRNAs are expressed abnormally suggesting they may be useful markers for diagnosis, prognosis, and potential therapeutic intervention in this disease. However, the contribution of individual miRNAs to the development and progression of this disease remains poorly understood. This study investigated the role of miR-24, which has not been extensively studied in relation to prostate cancer. METHODS We used PCR to investigate the expression of miR-24 in a panel of prostate cancer cell-lines and in a series of clinical prostate biopsy specimens. The biological significance of miR-24 expression in prostate cancer cells was assessed by a series of in vitro bioassays and the effect on proposed targets p27 (CDKN1B) and p16 (CDK2NA) was investigated. RESULTS We showed that miR-24 expression was significantly lower in prostate cancer cell lines compared to a normal prostate epithelial cell line. Decreased expression of miR-24 was also more frequently observed in both needle core and prostatectomy tumor tissue relative to matched normal tissue. Low miR-24 expression correlated with high PSA serum levels and other markers of increased prostate cancer progression. Importantly, over-expression of miR-24 inhibited cell cycle, proliferation, migration, and clonogenic potential of prostate cancer cells, as well as inducing apoptosis. p27 and p16 were confirmed as targets of miR-24 in prostate cancer cells and a significant inverse correlation between miR-24 and p27 was revealed in clinical prostatectomy specimens. CONCLUSIONS These findings provide evidence that miR-24 has a tumor suppressor role in prostate cancer and also targets p27 and p16 in prostate cancer cells. We propose that it may be a useful progression biomarker or focus of therapeutic intervention for this disease.
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Affiliation(s)
- Seodhna M Lynch
- Biomedical Sciences Research Institute, University of Ulster, Coleraine, Derry, United Kingdom
| | - Michael M McKenna
- Department of Cellular Pathology, Western Health and Social Care Trust, Altnagelvin Area Hospital, Derry, United Kingdom
| | - Colum P Walsh
- Biomedical Sciences Research Institute, University of Ulster, Coleraine, Derry, United Kingdom
| | - Declan J McKenna
- Biomedical Sciences Research Institute, University of Ulster, Coleraine, Derry, United Kingdom
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31
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Chandra V, Kim JJ, Mittal B, Rai R. MicroRNA aberrations: An emerging field for gallbladder cancer management. World J Gastroenterol 2016; 22:1787-1799. [PMID: 26855538 PMCID: PMC4724610 DOI: 10.3748/wjg.v22.i5.1787] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Revised: 11/12/2015] [Accepted: 12/21/2015] [Indexed: 02/06/2023] Open
Abstract
Gallbladder cancer (GBC) is infrequent but most lethal biliary tract malignancy characterized by an advanced stage diagnosis and poor survival rates attributed to absence of specific symptoms and effective treatment options. These necessitate development of early prognostic/predictive markers and novel therapeutic interventions. MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a key role in tumor biology by functioning like tumor suppressor- or onco- genes and their aberrant expression are associated with the pathogenesis of several neoplasms with overwhelming clinical implications. Since miRNA signature is tissue specific, here, we focused on current data concerning the miRNAs aberrations in GBC pathogenesis. In GBC, miRNAs with tumor suppressor activity (miR-135-5p, miR-335, miR-34a, miR-26a, miR-146b-5p, Mir-218-5p, miR-1, miR-145, mir-130a) were found downregulated, while those with oncogenic property (miR-20a, miR-182, mir-155) were upregulated. The expression profile of miRNAs was significantly associated with GBC prognosis and prediction, and forced over-expression/ inhibition of these miRNAs was shown to affect tumor growth and development. Further, differential expression of miRNAs in the blood samples of GBC patients suggest miRNAs as promising noninvasive biomarker. Thus, miRNAs represent potential candidate for GBC management, though many hurdles need to be overcome before miRNAs therapy can be clinically applied to GBC prevention and treatment.
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32
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Chen X, Fan S, Song E. Noncoding RNAs: New Players in Cancers. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 927:1-47. [PMID: 27376730 DOI: 10.1007/978-981-10-1498-7_1] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The world of noncoding RNAs (ncRNAs) has gained widespread attention in recent years due to their novel and crucial potency of biological regulation. Noncoding RNAs play essential regulatory roles in a broad range of developmental processes and diseases, notably human cancers. Regulatory ncRNAs represent multiple levels of structurally and functionally distinct RNAs, including the best-known microRNAs (miRNAs), the complicated long ncRNAs (lncRNAs), and the newly identified circular RNAs (circRNAs). However, the mechanisms by which they act remain elusive. In this chapter, we will review the current knowledge of the ncRNA field, discussing the genomic context, biological functions, and mechanisms of action of miRNAs, lncRNAs, and circRNAs. We also highlight the implications of the biogenesis and gene expression dysregulation of different ncRNA subtypes in the initiation and development of human malignancies.
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Affiliation(s)
- Xueman Chen
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, China
| | - Siting Fan
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, China
| | - Erwei Song
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang West Road, Guangzhou, China.
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Choi YS, Lee KE. The Significance of miR-34a Expression in Endometrial Carcinogenesis: Correlation With Expression of p16 and Ki-67 Proteins in Endometrial Cancers. J Cancer Prev 2015; 20:268-74. [PMID: 26734589 PMCID: PMC4699754 DOI: 10.15430/jcp.2015.20.4.268] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Revised: 10/30/2015] [Accepted: 10/30/2015] [Indexed: 02/05/2023] Open
Abstract
Background: A microRNA, miR-34a, plays a key role in inhibiting cellular transformation and carcinogenesis by controlling cell cycle regulation and cell proliferation in various human tumors. However, miR-34a has rarely been reported in endometrial cancer research in Korea. This study was undertaken to analyze miR-34a expression in simple endometrial hyperplasia and endometrial cancer, and to evaluate the relationship between expression of miR-34a and p16 and Ki-67 proteins in endometrial cancers. Methods: A retrospective study was carried out on 66 formalin-fixed, paraffin-embedded tissues with simple endometrial hyperplasia (31 cases) and endometrial cancer (35 cases) patients. These were analyzed for miR-34a expression by quantitative real-time PCR, and the expression of p16 and Ki-67 proteins in endometrial cancers was evaluated by immunohistochemistry. Results: The miR-34a expression level was lower in endometrial cancer tissues (−0.71 ± 3.90) than in simple endometrial hyperplasia tissues (2.68 ± 8.62). The endometrial hyperplasia tissues showed underexpression of miR-34a in 13 of the 31 cases (41.9%) while the endometrial cancer tissues showed underexpression of miR-34a in 24 of 35 cases (68.6%). Thus, miR-34a was significantly underexpressed in endometrial cancer tissues when compared endometrial hyperplasia tissues (P = 0.046). Overexpression of p16 was detected in 25 (71.4%) and Ki-67 immunoreactivity was detected in 27 (77.1%) of the 35 endometrial cancers. Although not statistically significant, the frequency of p16 and Ki-67 overexpression tended to be lower in the cases with miR-34a underexpression than in cases with miR-34a overexpression. Conclusions: These findings suggest that underexpression of miR-34a might be involved in endometrial carcinogenesis. Further studies are needed to define the relationship between miR-34a expression and tissue specific protein expression.
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Affiliation(s)
- Yoon Sung Choi
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, Korea
| | - Kyung Eun Lee
- Department of Clinical Laboratory Science, College of Health Sciences, Catholic University of Pusan, Busan, Korea
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Mao L, Li J, Chen WX, Cai YQ, Yu DD, Zhong SL, Zhao JH, Zhou JW, Tang JH. Exosomes decrease sensitivity of breast cancer cells to adriamycin by delivering microRNAs. Tumour Biol 2015; 37:5247-56. [DOI: 10.1007/s13277-015-4402-2] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2015] [Accepted: 11/05/2015] [Indexed: 12/20/2022] Open
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35
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Zheng X, Li J, Peng C, Zhao J, Chi J, Meng X, Yun X, Li D, Yu Y, Gao M, Li Y. MicroRNA-24 induces cisplatin resistance by targeting PTEN in human tongue squamous cell carcinoma. Oral Oncol 2015; 51:998-1003. [DOI: 10.1016/j.oraloncology.2015.08.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 07/03/2015] [Accepted: 08/04/2015] [Indexed: 12/25/2022]
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Biomolecular bases of the senescence process and cancer. A new approach to oncological treatment linked to ageing. Ageing Res Rev 2015; 23:125-38. [PMID: 25847820 DOI: 10.1016/j.arr.2015.03.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 03/30/2015] [Indexed: 01/07/2023]
Abstract
Human ageing is associated with a gradual decline in the physiological functions of the body at multiple levels and it is a key risk factor for many diseases, including cancer. Ageing process is intimately related to widespread cellular senescence, characterised by an irreversible loss of proliferative capacity and altered functioning associated with telomere attrition, accumulation of DNA damage and compromised mitochondrial and metabolic function. Tumour and senescent cells may be generated in response to the same stimuli, where either cellular senescence or transformation would constitute two opposite outcomes of the same degenerative process. This paper aims to review the state of knowledge on the biomolecular relationship between cellular senescence, ageing and cancer. Importantly, many of the cell signalling pathways that are found to be altered during both cellular senescence and tumourigenesis are regulated through shared epigenetic mechanisms and, therefore, they are potentially reversible. MicroRNAs are emerging as pivotal players linking ageing and cancer. These small RNA molecules have generated great interest from the point of view of future clinical therapy for cancer because successful experimental results have been obtained in animal models. Micro-RNA therapies for cancer are already being tested in clinical phase trials. These findings have potential importance in cancer treatment in aged people although further research-based knowledge is needed to convert them into an effective molecular therapies for cancer linked to ageing.
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Kropp J, Khatib H. Characterization of microRNA in bovine in vitro culture media associated with embryo quality and development. J Dairy Sci 2015; 98:6552-63. [PMID: 26142856 DOI: 10.3168/jds.2015-9510] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 05/13/2015] [Indexed: 01/08/2023]
Abstract
Dairy cattle fertility has declined over time due to factors including reduced fertilization and early embryonic loss. To counter fertility problems and better study preimplantation embryonic development, in vitro production systems have been developed. These systems largely assess embryos based on their morphology, which is not a strong indicator of developmental potential. Currently, no biomarkers can be used to noninvasively survey an embryo's potential in terms of its development and ability to establish a pregnancy. Thus, the objective of this study was to characterize and identify microRNA (miRNA) in culture media of embryos of differing developmental competence for future development as noninvasive biomarkers of embryo quality. The MiRNA sequencing of media conditioned by blastocyst and degenerate (those that failed to develop from the morula to blastocyst stage) embryos, revealed 11 differentially expressed miRNA; all were higher in concentration in degenerate conditioned media. Differential expression of mature microRNA (miR)-24, miR-191, and miR-148a was further validated using quantitative real-time PCR. Functional analysis of miR-24 revealed that addition of a mimic miRNA to culture media of morulae embryos resulted in a 27.3% decrease in development to the blastocyst stage. Furthermore, expression of miR-24 was 44.29-fold higher in blastocysts cultured with a miR-24 mimic compared with control blastocysts. Interestingly, the expression of CDKN1b, a target gene of miR-24 was repressed in embryos grown in the presence of the miRNA mimic. Mimic supplementation experiments suggest that miRNA are taken up by the embryo and that extracellular miRNA affect embryonic development. Overall, identification of a rich extracellular milieu in conditioned media sets the framework for future studies to determine the long-term predictive ability of embryo-based miRNA biomarkers on pregnancy outcome.
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Affiliation(s)
- Jenna Kropp
- Department of Animal Sciences, University of Wisconsin, Madison 53706
| | - Hasan Khatib
- Department of Animal Sciences, University of Wisconsin, Madison 53706.
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Affiliation(s)
- Araika Gutiérrez-Rivera
- Tissue Engineering Laboratory, Instituto Biodonostia, Hospital Universitario Donostia, San Sebastian, Spain
| | - Ander Izeta
- Tissue Engineering Laboratory, Instituto Biodonostia, Hospital Universitario Donostia, San Sebastian, Spain
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39
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Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients. Br J Cancer 2015; 113:69-75. [PMID: 26057448 PMCID: PMC4647524 DOI: 10.1038/bjc.2015.187] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 04/21/2015] [Accepted: 04/28/2015] [Indexed: 12/25/2022] Open
Abstract
Background: Malignant pleural mesothelioma (MPM) is a rare and essentially incurable malignancy most often linked with occupational exposure to asbestos fibres. In common with other malignancies, the development and progression of MPM is associated with extensive dysregulation of cell cycle checkpoint proteins that modulate cell proliferation, apoptosis, DNA repair and senescence. Methods: The expression of cyclin-dependent kinase inhibitor p16/INK4A was evaluated by immunohistochemistry using tumour biopsy specimens from 88 MPM cases and a semi-quantitative score for p16/INK4A expression was obtained. Post-diagnosis survival and the survival benefit of chemotherapeutic intervention was correlated with p16/INK4A expression. Results: A low, intermediate and high score for p16/INK4A expression was observed for 45 (51.1%), 28 (31.8%) and 15 (17.1%) of the MPM cases, respectively. Those cases with intermediate or high p16/INK4A tumour expression had a significantly better post-diagnosis survival than those cases whose tumours lost p16 expression (log-rank P<0.001). Those patients with sustained p16/INK4A expression who received chemotherapy also had a better survival than those treated patients whose tumours had lost p16/INK4A expression (log-rank P<0.001). Conclusions: Sustained p16/INK4A expression predicts better post-diagnosis survival in MPM and also better survival following chemotherapeutic intervention.
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Fuentes E, Palomo I, Alarcón M. Platelet miRNAs and cardiovascular diseases. Life Sci 2015; 133:29-44. [PMID: 26003375 DOI: 10.1016/j.lfs.2015.04.016] [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: 01/20/2015] [Revised: 03/25/2015] [Accepted: 04/21/2015] [Indexed: 01/04/2023]
Abstract
Activated platelets play a critical role in the acute complications of atherosclerosis that cause life-threatening ischemic events at late stages of the disease. The miRNAs are a novel class of small, non-coding RNAs that play a significant role in both inflammatory and cardiovascular diseases. The miRNAs are known to be present in platelets and exert important regulatory functions. Here we systematically examine the genes that are regulated by platelet miRNAs (miRNA-223,miRNA-126,miRNA-21, miRNA-24 and miRNA-197) and the association with cardiovascular disease risks. Platelet-secreted miRNAs could be novel biomarkers associated with cardiovascular diseases.
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Affiliation(s)
- Eduardo Fuentes
- Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), Universidad de Talca, Talca, Chile; Centro de Estudios en Alimentos Procesados (CEAP), CONICYT-Regional, Gore Maule R09I2001, Chile
| | - Iván Palomo
- Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), Universidad de Talca, Talca, Chile; Centro de Estudios en Alimentos Procesados (CEAP), CONICYT-Regional, Gore Maule R09I2001, Chile.
| | - Marcelo Alarcón
- Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), Universidad de Talca, Talca, Chile; Centro de Estudios en Alimentos Procesados (CEAP), CONICYT-Regional, Gore Maule R09I2001, Chile.
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41
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Song Z, Liu D, Peng Y, Li J, Zhang Z, Ning P. Differential microRNA expression profile comparison between epidermal stem cells and differentiated keratinocytes. Mol Med Rep 2015; 11:2285-2291. [PMID: 25373715 DOI: 10.3892/mmr.2014.2886] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2013] [Accepted: 09/12/2014] [Indexed: 11/06/2022] Open
Abstract
The aim of the current study was to analyze the differential microRNA (miRNA) expression profiles of human epidermal stem cells (ESCs) and differentiated keratinocytes. Enzyme digestion was used in combination with rapid adhesion to collagen IV to isolate primary human ESCs and differentiated keratinocytes, from which total RNA was extracted. Fluorescence labeling, microarray hybridization and differential expression analyses were performed. Reverse transcription quantitative polymerase chain reaction (RT‑qPCR) was performed to validate the reliability of the microarray results and predict the target genes of the differentially expressed miRNAs. A total of 25 miRNAs, including hsa‑miR‑197‑5p, hsa‑miR‑125b‑5p and hsa‑miR‑376a‑3p, were upregulated, whereas 166 miRNAs, including hsa‑miR‑29b‑3p, hsa‑miR‑203 and hsa‑miR‑34a‑3p, were downregulated in the human ESCs compared with the expression in differentiated keratinocytes. RT‑qPCR results confirmed the upregulation of hsa‑miR‑197‑5p and the downregulation of hsa‑miR‑29b‑3p, which were consistent with the microarray results. miRNA target prediction indicated that the miRNA expression levels correlated with cell proliferation, differentiation, apoptosis and senescence. Expression levels of miRNAs significantly differed between human ESCs and differentiated keratinocytes. This finding may be attributed to their biological characteristics, such as proliferative behavior and differentiation abilities.
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Affiliation(s)
- Zhifang Song
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Dewu Liu
- Burn Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yan Peng
- Burn Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Jin Li
- Burn Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zhiwei Zhang
- Burn Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Pu Ning
- Burn Center, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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42
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Redshaw Z, Sweetman D, Loughna PT. The effects of age upon the expression of three miRNAs in muscle stem cells isolated from two different porcine skeletal muscles. Differentiation 2014; 88:117-23. [PMID: 25542334 DOI: 10.1016/j.diff.2014.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Revised: 11/13/2014] [Accepted: 12/02/2014] [Indexed: 01/31/2023]
Abstract
Aging is associated with a gradual loss of skeletal muscle mass and an impaired ability of this tissue to compensate for trauma. Studies in rodents and humans have also shown that resident stem cells within muscle have a reduced ability to proliferate and differentiate. In this study muscle stem cells have been isolated from two muscles, the diaphragm (DIA) and the semimembranosus (SM), from young and old pigs. The levels of three micro-RNAs (miRNAs) were measured when cells were in a proliferative phase and after 24 and 72h in differentiation medium. All three miRNAs are abundant in skeletal muscle with miR-1 and miR-206 known to regulate myogenic differentiation and miR-24 is involved in cell cycle regulation. The levels of expression of Pax7 and the myogenic regulatory factors MyoD and myogenin were also measured. There were marked differences in expression of all three miRNAs between the two age groups. Both miR-1 and miR-206 were reduced in the cells from the older animals. In contrast miR-24 expression was significantly higher in cells from older animals under differentiation conditions. There were also significant differences in the relative expression of all three miRNAs between cells from the SM and DIA in both young and old animals. The changes in miRNA expression described in this study that relate to age, may play a role in the impaired differentiation capacity of older muscle stem cells.
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Affiliation(s)
- Zoe Redshaw
- School of Veterinary Medicine and Science, The University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire LE12 5RD, United Kingdom.
| | - Dylan Sweetman
- School of Biosciences, The University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire LE12 5RD, United Kingdom.
| | - Paul T Loughna
- School of Veterinary Medicine and Science, The University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Leicestershire LE12 5RD, United Kingdom.
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43
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Gao Y, Liu Y, Du L, Li J, Qu A, Zhang X, Wang L, Wang C. Down-regulation of miR-24-3p in colorectal cancer is associated with malignant behavior. Med Oncol 2014; 32:362. [DOI: 10.1007/s12032-014-0362-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 11/13/2014] [Indexed: 01/21/2023]
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Ma Y, She XG, Ming YZ, Wan QQ. miR-24 promotes the proliferation and invasion of HCC cells by targeting SOX7. Tumour Biol 2014; 35:10731-10736. [PMID: 25073511 DOI: 10.1007/s13277-014-2018-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Accepted: 04/23/2014] [Indexed: 01/19/2023] Open
Abstract
Accumulating evidence shows that microRNAs (miRNAs) are involved in the development and progression of multiple tumors, including hepatocellular carcinoma (HCC). Recent studies have found that miR-24 acts as an oncogene in several tumors; however, the function of miR-24 in HCC remains unclear. In this study, we found that miR-24 was increased in HCC tissues and cell lines. Inhibition of miR-24 by inhibitor significantly suppressed HCC cells proliferation, migration, and invasion. Furthermore, the sex-determining region Y (SRY)-box 7 (SOX7), a putative tumor suppressor, was found to be a target of miR-24 in HCC cells. Forced expression of SOX7 substantially attenuated the oncogenic effects of miR-24. Those results strongly suggest that miR-24 plays important role in HCC development partially by targeting SOX7.
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Affiliation(s)
- Ying Ma
- Departments of Transplant Surgery, the Third Affiliated Hospital, Central South University, Hunan, China
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Hamdi K, Goerlitz D, Stambouli N, Islam M, Baroudi O, Neili B, Benayed F, Chivi S, Loffredo C, Jillson IA, Benammar Elgaaied A, Blancato JK, Marrakchi R. miRNAs in Sera of Tunisian patients discriminate between inflammatory breast cancer and non-inflammatory breast cancer. SPRINGERPLUS 2014; 3:636. [PMID: 26034677 PMCID: PMC4447743 DOI: 10.1186/2193-1801-3-636] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 09/15/2014] [Indexed: 01/04/2023]
Abstract
In recent years, circulating miRNAs have attracted interest as stable, non-invasive biomarkers for various pathological conditions. Here, we investigated their potential to serve as minimally invasive, early detection markers for inflammatory breast cancer (IBC) and non-inflammatory breast cancer (non-IBC) in serum. miRNA profiling was performed on serum from 20 patients with non-IBC, 20 with IBC, and 20 normal control subjects. Real-time reverse transcription-polymerase chain reaction (qRT-PCR) was applied to measure the level of 12 candidate miRNAs previously identified in other research(miR-342-5p, miR-342--3p, miR-320, miR-30b, miR-29a, miR-24, miR-15a, miR-548d-5p, miR-486-3p, miR-451, miR-337-5p, miR-335).We found that 4 miRNAs (miR-24, miR-342-3p, miR-337-5p and miR-451) were differentially expressed in serum of IBC patients compared to non-IBC, and 3 miRNAs (miR-337-5p ,miR-451and miR-30b) were differentially expressed in IBC and non-IBC patients combined compared to healthy controls. miR-24, miR-342-3p, miR-337-5p and miR-451 were found to be significantly down-regulated in IBC patients compared to non-IBC. Likewise, the expression level of mir-451 showed significant down-regulation in IBC serum, while mir-30b and miR-337-5p were up-regulated in non-IBC serum comparatively to normal controls. Using receiver operational curve (ROC) analysis, we show that dysregulated miRNAs can discriminate patients with IBC and non-IBC from healthy controls with sensitivity ranging from 76 to 81% and specificity from 66 to 80%, for three separate miRNAs. In conclusion, our data suggest that circulating miRNAs are potential biomarkers for classifying IBC and non-IBC, and may also be candidates for early detection of breast cancer.
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Affiliation(s)
- Khouloud Hamdi
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences, University of Tunis El Manar, El Mannar I, Tunis, 2092 Tunisia
| | - David Goerlitz
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007 USA
| | - Neila Stambouli
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences, University of Tunis El Manar, El Mannar I, Tunis, 2092 Tunisia
| | - Mohammed Islam
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007 USA
| | - Olfa Baroudi
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences, University of Tunis El Manar, El Mannar I, Tunis, 2092 Tunisia
| | - Bilel Neili
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences, University of Tunis El Manar, El Mannar I, Tunis, 2092 Tunisia
| | - Farhat Benayed
- Department of Medical Oncology, Hannibal International Clinic, Les Berges du Lac 2, Tunis, Tunisia
| | - Simon Chivi
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007 USA
| | - Christopher Loffredo
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007 USA
| | - Irene A Jillson
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007 USA
| | - Amel Benammar Elgaaied
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences, University of Tunis El Manar, El Mannar I, Tunis, 2092 Tunisia
| | - Jan K Blancato
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007 USA
| | - Raja Marrakchi
- Laboratory of Genetics, Immunology and Human Pathology, Faculty of Sciences, University of Tunis El Manar, El Mannar I, Tunis, 2092 Tunisia
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Katoh M. Cardio-miRNAs and onco-miRNAs: circulating miRNA-based diagnostics for non-cancerous and cancerous diseases. Front Cell Dev Biol 2014; 2:61. [PMID: 25364765 PMCID: PMC4207049 DOI: 10.3389/fcell.2014.00061] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 09/29/2014] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular diseases and cancers are the leading causes of morbidity and mortality in the world. MicroRNAs (miRNAs) are short non-coding RNAs that primarily repress target mRNAs. Here, miR-24, miR-125b, miR-195, and miR-214 were selected as representative cardio-miRs that are upregulated in human heart failure. To bridge the gap between miRNA studies in cardiology and oncology, the targets and functions of these miRNAs in cardiovascular diseases and cancers will be reviewed. ACVR1B, BCL2, BIM, eNOS, FGFR3, JPH2, MEN1, MYC, p16, and ST7L are miR-24 targets that have been experimentally validated in human cells. ARID3B, BAK1, BCL2, BMPR1B, ERBB2, FGFR2, IL6R, MUC1, SITR7, Smoothened, STAT3, TET2, and TP53 are representative miR-125b targets. ACVR2A, BCL2, CCND1, E2F3, GLUT3, MYB, RAF1, VEGF, WEE1, and WNT7A are representative miR-195 targets. BCL2L2, ß-catenin, BIM, CADM1, EZH2, FGFR1, NRAS, PTEN, TP53, and TWIST1 are representative miR-214 targets. miR-125b is a good cardio-miR that protects cardiomyocytes; miR-195 is a bad cardio-miR that elicits cardiomyopathy and heart failure; miR-24 and miR-214 are bi-functional cardio-miRs. By contrast, miR-24, miR-125b, miR-195, and miR-214 function as oncogenic or tumor suppressor miRNAs in a cancer (sub)type-dependent manner. Circulating miR-24 is elevated in diabetes, breast cancer and lung cancer. Circulating miR-195 is elevated in acute myocardial infarction, breast cancer, prostate cancer and colorectal adenoma. Circulating miR-125b and miR-214 are elevated in some cancers. Cardio-miRs and onco-miRs bear some similarities in functions and circulation profiles. miRNAs regulate WNT, FGF, Hedgehog and other signaling cascades that are involved in orchestration of embryogenesis and homeostasis as well as pathogenesis of human diseases. Because circulating miRNA profiles are modulated by genetic and environmental factors and are dysregulated by genetic and epigenetic alterations in somatic cells, circulating miRNA association studies (CMASs) within several thousands of cases each for common non-cancerous diseases and major cancers are necessary for miRNA-based diagnostics.
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Affiliation(s)
- Masaru Katoh
- Department of Omics Network, National Cancer Center Tokyo, Japan
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47
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Riemondy K, Hoefert JE, Yi R. Not miR-ly micromanagers: the functions and regulatory networks of microRNAs in mammalian skin. WILEY INTERDISCIPLINARY REVIEWS-RNA 2014; 5:849-65. [PMID: 25044412 DOI: 10.1002/wrna.1250] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Revised: 05/16/2014] [Accepted: 05/22/2014] [Indexed: 01/20/2023]
Abstract
The microRNA (miRNA) pathway is a widespread mechanism of post-transcriptional gene regulation in eukaryotic cells. In animals, each miRNA species can regulate hundreds of protein-coding genes, resulting in pervasive functions for miRNAs in numerous cellular processes. Since the identification of the first mammalian miRNA, the function of miRNAs in mammals has been a topic of great interest, both because of the versatile roles of miRNAs in biological systems, as well as the clinical potential of these regulatory RNAs. With well-defined cell lineages and the availability of versatile tools for both in vivo and in vitro studies, mammalian skin has emerged as an important system in which to examine miRNAs' functions in adult tissues. In this review, we discuss recent insights into the functions and regulatory networks of miRNAs in mammals, with a specific focus on murine skin development as a model system. We first introduce functional analyses of the miRNA biogenesis pathway in the skin, then highlight the functions of individual miRNAs in skin development, followed by an examination of miRNA roles in skin stress responses. We finish with a discussion of miRNA regulatory networks and emphasize future challenges and emerging technologies that permit the genome-wide study of miRNA functions and regulatory mechanisms in mammalian skin.
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Affiliation(s)
- Kent Riemondy
- Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO, USA
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48
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Di Gregoli K, Jenkins N, Salter R, White S, Newby AC, Johnson JL. MicroRNA-24 regulates macrophage behavior and retards atherosclerosis. Arterioscler Thromb Vasc Biol 2014; 34:1990-2000. [PMID: 24990232 DOI: 10.1161/atvbaha.114.304088] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Our recent studies have highlighted membrane type-1 matrix metalloproteinase (MMP)-14 as a selective marker for an invasive subset of macrophages potentially related to atherosclerotic plaque progression. Moreover, colony stimulating factors (CSF) may exert divergent effects on macrophage MMP expression, possibly through microRNAs. We, therefore, aim to identify and test the pathophysiological role of microRNAs, which modulate macrophage MMP-14 expression in atherosclerotic plaque progression. APPROACH AND RESULTS Compared with macrophage CSF-differentiated macrophages, granulocyte/macrophage CSF-matured macrophages exhibited reduced MMP-14 mRNA levels but increased protein expression and activity, which resulted in heightened macrophage invasion. MicroRNA-24, identified to target MMP-14, was accordingly increased in macrophage CSF compared with granulocyte/macrophage CSF macrophages. Silencing microRNA-24 in macrophage CSF macrophages significantly increased MMP-14 expression and enhanced their invasive capacity, mimicking granulocyte/macrophage CSF macrophages, and suggesting that granulocyte/macrophage CSF modulates MMP-14 protein expression and subsequent macrophage invasion in a microRNA-24-dependent manner. In human coronary atherosclerotic plaques, increased MMP-14 protein expression in foam cell macrophages was associated with lesions exhibiting histological characteristics associated with an unstable phenotype. Furthermore, microRNA-24 expression in these atherosclerotic plaques was inversely related to MMP-14 protein expression. Moreover, stable plaques contained higher microRNA-24 levels than unstable plaques, and microRNA-24 colocalized with foam cell macrophages that exhibited low MMP-14 protein expression. Finally, in atherosclerotic mice (apolipoprotein E-deficient), microRNA-24 inhibition increased plaque size and macrophage MMP-14 expression. CONCLUSIONS Taken together, our data demonstrates that downregulation of microRNA-24 promotes an invasive macrophage subset and plays a novel regulatory role in MMP-14 proteolytic activity and, therefore, plaque stability, highlighting its therapeutic potential.
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Affiliation(s)
- Karina Di Gregoli
- From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom
| | - Nicholas Jenkins
- From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom
| | - Rebecca Salter
- From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom
| | - Stephen White
- From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom
| | - Andrew C Newby
- From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom
| | - Jason L Johnson
- From the School of Clinical Sciences, University of Bristol, Bristol, England, United Kingdom.
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Abstract
Menin, the product of the MEN1 gene, functions as a tumor suppressor and was first identified in 1997 due to its causative role in the endocrine tumor disorder multiple endocrine neoplasia, type 1 (MEN1). More recently, menin has been identified as a key player in pancreatic islet biology with the observation of an inverse relationship between menin levels and pancreatic islet proliferation. However, the factors regulating menin and the MEN1 gene in the pancreas are poorly understood. Here, we describe the regulation of menin by miR-24 and demonstrate that miR-24 directly decreases menin levels and impacts downstream cell cycle inhibitors in MIN6 insulinoma cells and in βlox5 immortalized β-cells. This regulation of menin impacts cell viability and proliferation in βlox5 cells. Furthermore, our data show a feedback regulation between miR-24 and menin that is present in the pancreas, suggesting that miR-24 regulates menin levels in the pancreatic islet.
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Affiliation(s)
- Jyothi Vijayaraghavan
- Department of Genetics, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Elaine C Maggi
- Department of Genetics, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana
| | - Judy S Crabtree
- Department of Genetics, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana
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50
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Wang XH, Cai P, Wang MH, Wang Z. microRNA‑25 promotes osteosarcoma cell proliferation by targeting the cell‑cycle inhibitor p27. Mol Med Rep 2014; 10:855-9. [PMID: 24859599 DOI: 10.3892/mmr.2014.2260] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Accepted: 04/24/2014] [Indexed: 11/05/2022] Open
Abstract
An increasing body of evidence indicates that microRNAs (miRNAs), a class of small non‑coding RNAs, are often aberrantly expressed in human osteosarcoma. This study aimed to investigate the effects of miR‑25 and to identify its potential target genes in osteosarcoma (OS) cells. First, the expression of miR‑25 was detected by reverse transcription‑quantitative polymerase chain reaction (RT-qPCR), which revealed a significant upregulation of miR‑25 in osteosarcoma tissues compared to the adjacent healthy tissues. To investigate the role of miR‑25 in osteosarcoma cell proliferation, the miR‑25 precursor was next transfected into Saos‑2 and U2OS cells. Overexpression of miR‑25 promoted cell proliferation in vitro and tumor growth in a xenograft mouse model. In addition, our results revealed that the protein expression of p27, a cell‑cycle inhibitor, is negatively regulated by miR‑25. Restoring the p27 level in miR‑25‑overexpressing cells reversed the enhancing effect of miR‑25 on cell proliferation. Therefore, miR‑25 may act as an onco‑miRNA in osteosarcoma, which provides new perspectives in cancer treatment strategies based on molecular targeting.
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Affiliation(s)
- Xiu-Hui Wang
- Department of Orthopaedics, Pudong New Area Zhoupu Hospital, Shanghai 201318, P.R. China
| | - Pan Cai
- Department of Orthopaedics, Pudong New Area Zhoupu Hospital, Shanghai 201318, P.R. China
| | - Ming-Hui Wang
- Department of Orthopaedics, Pudong New Area Zhoupu Hospital, Shanghai 201318, P.R. China
| | - Zhe Wang
- Clinical Medical College, China Medical University, Shenyang, Liaoning 110001, P.R. China
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