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Hofsli E, Sætrom P, Ness-Jensen E, Surcel HM, Mjelle R. Can circulating microRNAs predict colorectal cancer? Results from a nested case-control study of pre-diagnostic serum samples from two prospective biobanks. BMC Cancer 2025; 25:455. [PMID: 40082755 PMCID: PMC11905635 DOI: 10.1186/s12885-025-13854-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 03/03/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND This study aimed to investigate the potential of circulating small RNAs (sRNAs) as predictive biomarkers for future colorectal cancer (CRC). The study analyzed serum samples from pre-diagnostic CRC patients in two prospective biobanks. METHODS Serum samples from 142 pre-diagnostic CRC patients, from the Finnish Maternity Cohort (FMC) and The HUNT Study (HUNT2), were subjected to small RNA sequencing. The study compared sRNA expression in CRC cases with controls, considering diverse sRNA classes. RESULTS Analysis revealed diverse miRNA expression patterns with notable variations in future metastatic cases. Specifically, miR-223-3p and miR-21-5p showed significant up-regulation in future metastatic cases in the FMC cohort. Consistent changes were observed across cohorts, with miR-584-5p, miR-30c-5p, miR-146a-5p, miR-10a-5p, and miR-1306-5p showing up-regulation in future metastatic cases. CONCLUSIONS The study identified potential serum miRNA biomarkers associated with metastatic CRC, though statistical significance varied. These findings contribute to the understanding of miRNA profiles in pre-diagnostic CRC patients, emphasizing the need for further exploration of non-invasive biomarkers in large prospective studies.
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Affiliation(s)
- Eva Hofsli
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Oncology, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Pål Sætrom
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- St. Olavs Hospital HF, Sentral Stab, Trondheim, NO-7006, Norway
- Department of Computer Science, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
- K.G.Jebsen Center for Genetic Epidemiology, NTNU - Norwegian University of Science and Technology, Trondheim, NO-7491, Norway
| | - Eivind Ness-Jensen
- HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, Norway
- Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
- HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Helja-Marja Surcel
- Biobank Borealis of Northern Finland, Oulu University Hospital, Oulu, Finland
- Faculty of Medicine, University of Oulu, Oulu, Finland
| | - Robin Mjelle
- Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
- Department of Pathology, St.Olav's Hospital, Laboratoriesenteret 4, Etg Erling Skjalgssons Gate 1, Trondheim, 7030, Norway.
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Geisler L, Detjen K, Hellberg T, Kohlhepp M, Grötzinger C, Knorr J, Eichhorn I, Mohr R, Holtmann T, Wiedenmann B, Tacke F, Roderburg C, Wree A. miR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine Neoplasms. Cells 2025; 14:111. [PMID: 39851539 PMCID: PMC11763622 DOI: 10.3390/cells14020111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/08/2025] [Accepted: 01/08/2025] [Indexed: 01/26/2025] Open
Abstract
Neuroendocrine neoplasms (NENs) are a diverse group originating from endocrine cells/their precursors in pancreas, small intestine, or lung. The key serum marker is chromogranin A (CgA). While commonly elevated in patients with NEN, its prognostic value is still under discussion. Secretion/posttranslational proteolytic cleavage of CgA results in multiple bioactive fragments, which are essential regulators of the cardiovascular and immune system. miR-223, regulator of Nrlp3 inflammasome and neutrophil activation, was recently found to have decreased in patients with NEN. We performed flow cytometry of circulating neutrophils in a patient cohort (n = 10) with NEN, microdissection and histology of tumor tissue. Subsequently, in vitro transfections using the well-established human pancreatic NEN cell line (BON), and co-culture experiments with primary macrophages and neutrophils were performed. Serum miR-223 in patients correlated with the expression of the neutrophil activation marker CD15 in circulating cells. Neutrophilic CD62L/CD63 showed good discrimination compared to healthy controls. Immune cell-derived miR-155, miR-193 and miR-223 colocalize with neutrophil in the extra-tumoral tissue alongside Nlrp3-associated caspase-1 activation. miR-223 knockdown in BON decreased the CgA intracellularly, increased in cellular granularity and caspase-1 activation. Plasmin inhibitor a2-aP reverted those effects. Western Blot showed fragmented CgA following miR-223 knockdown, which altered the inflammatory potential of neutrophils. Our data hence provide initial insights into an immunoregulatory mechanism via miR-223 and CgA in NEN cells, as regulation of miR-223 in NEN may affect tumor-associated inflammation.
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Affiliation(s)
- Lukas Geisler
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
- Department of Biology, Humboldt University of Berlin, 10099 Berlin, Germany
| | - Katharina Detjen
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Teresa Hellberg
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Marlene Kohlhepp
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Carsten Grötzinger
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Jana Knorr
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Ines Eichhorn
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Raphael Mohr
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Theresa Holtmann
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Bertram Wiedenmann
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Christoph Roderburg
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, 40225 Düsseldorf, Germany
| | - Alexander Wree
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
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Nanoudis S, Yavropoulou MP, Tsachouridou O, Pikilidou M, Pilalas D, Kotsa K, Skoura L, Zebekakis P, Metallidis S. Circulating MicroRNAs Related to Arterial Stiffness in Adults with HIV Infection. Viruses 2024; 16:1945. [PMID: 39772253 PMCID: PMC11680088 DOI: 10.3390/v16121945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 12/15/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
People with HIV (PWH) have an elevated risk of cardiovascular disease compared to those without HIV. This study aimed to investigate the relative serum expression of microRNAs (miRNAs) associated with arterial stiffness, a significant marker of cardiovascular disease. A total of 36 male PWH and 36 people without HIV, matched for age, body mass index, pack years, and dyslipidemia, were included in the study. Participants with a history of hypertension, diabetes mellitus, cardiovascular disease, cancer, or intravenous drug use were excluded. Markers of arterial stiffness, including carotid-femoral pulse wave velocity (cfPWV) and augmentation index adjusted to 75 beats per minute (AIx@75), were measured via applanation tonometry. We analyzed the relative expression of 11 circulating miRNAs using real-time PCR: let-7b-5p, miR-19b-3p, miR-21-5p, miR-29a-3p, miR-126-3p, miR-130a-3p, miR-145-5p, miR-181b-5p, miR-221-3p, miR-222-3p, and miR-223-3p. cfPWV was significantly higher in PWH compared to people without HIV (9.3 vs. 8.6 m/s, p = 0.019), while AIx@75, peripheral, and aortic blood pressures did not differ among groups. The relative expression of circulating miRNAs was significantly higher in PWH compared to controls for let-7b-5p (fold change: 5.24, p = 0.027), miR-21-5p (fold change: 3.41, p < 0.001), miR-126-3p (fold change: 1.23, p = 0.019), and miR-222-3p (fold change: 3.31, p = 0.002). Conversely, the relative expression of circulating miR-19b-3p was significantly lower in PWH (fold change: 0.61, p = 0.049). Among HIV-related factors, the nadir CD4+T-cell count of <200 cells/mm3 was independently associated with the relative expression of circulating let-7b-5p (β = 0.344, p = 0.049), while current non-nucleoside reverse transcriptase inhibitor (NNRTI) treatment was independently associated with the relative expression of circulating miR-126-3p (β = 0.389, p = 0.010). No associations were found between the duration of HIV infection or the duration of ART and the serum miRNA expression. This study highlights a distinct circulating miRNA profile in PWH with higher cfPWV compared to those without HIV, which may contribute to increased arterial stiffness.
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Affiliation(s)
- Sideris Nanoudis
- 1st Internal Medicine Department, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 55436 Thessaloniki, Greece; (S.N.); (M.P.Y.); (M.P.); (D.P.); (K.K.); (P.Z.); (S.M.)
| | - Maria P. Yavropoulou
- 1st Internal Medicine Department, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 55436 Thessaloniki, Greece; (S.N.); (M.P.Y.); (M.P.); (D.P.); (K.K.); (P.Z.); (S.M.)
| | - Olga Tsachouridou
- 1st Internal Medicine Department, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 55436 Thessaloniki, Greece; (S.N.); (M.P.Y.); (M.P.); (D.P.); (K.K.); (P.Z.); (S.M.)
| | - Maria Pikilidou
- 1st Internal Medicine Department, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 55436 Thessaloniki, Greece; (S.N.); (M.P.Y.); (M.P.); (D.P.); (K.K.); (P.Z.); (S.M.)
| | - Dimitrios Pilalas
- 1st Internal Medicine Department, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 55436 Thessaloniki, Greece; (S.N.); (M.P.Y.); (M.P.); (D.P.); (K.K.); (P.Z.); (S.M.)
| | - Kalliopi Kotsa
- 1st Internal Medicine Department, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 55436 Thessaloniki, Greece; (S.N.); (M.P.Y.); (M.P.); (D.P.); (K.K.); (P.Z.); (S.M.)
| | - Lemonia Skoura
- Department of Microbiology, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 55436 Thessaloniki, Greece;
| | - Pantelis Zebekakis
- 1st Internal Medicine Department, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 55436 Thessaloniki, Greece; (S.N.); (M.P.Y.); (M.P.); (D.P.); (K.K.); (P.Z.); (S.M.)
| | - Symeon Metallidis
- 1st Internal Medicine Department, AHEPA University Hospital, School of Medicine, Aristotle University of Thessaloniki, 55436 Thessaloniki, Greece; (S.N.); (M.P.Y.); (M.P.); (D.P.); (K.K.); (P.Z.); (S.M.)
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Kavarthapu R, Lou H, Pham T, Do H, Soliman ME, Badger T, Balasubramanian R, Huyhn V, De La Luz Sierra M, Yano Maher JC, Gomez‐Lobo V. Single-nucleus and spatial transcriptomics of paediatric ovary: Molecular insights into the dysregulated signalling pathways underlying premature ovarian insufficiency in classic galactosemia. Clin Transl Med 2024; 14:e70043. [PMID: 39440457 PMCID: PMC11812122 DOI: 10.1002/ctm2.70043] [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: 06/24/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Classic galactosemia (CG) is an inborn error of galactose metabolism caused by mutations in the GALT gene. Premature ovarian insufficiency (POI) is a later complication that affects 80% of women with CG due to a significant decline in ovarian reserve (primordial follicle pool). The definite mechanisms underlying the early onset of POI in CG patients are not fully understood. METHODS In this study, we performed single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics on ovary tissue biopsies from prepubertal girls diagnosed with CG to investigate dynamic changes in gene expression and altered signalling pathways in granulosa cells, oocytes, and stromal cells. RESULTS We generated single-nucleus and spatial transcriptomics atlas of human ovaries from prepubertal girls diagnosed with and without CG. snRNA-seq profiling of the paediatric ovary revealed a diverse ovarian microenvironment with seven distinct major cell types. Our transcriptomic analysis revealed an increase in the expression of several endoplasmic reticulum stress and oxidative stress associated genes, which can promote apoptosis of granulosa cells in CG. PTEN/PI3K/AKT signalling, which is crucial for primordial follicle activation and survival was dysregulated as supported by upregulated PTEN transcripts and a significant reduction in phospho-AKT levels in the granulosa cells and oocytes. We also found a marked increase in expression of phospho-H2A.X, LC3A/B and CASP9 in the primordial follicles of CG ovaries suggesting DNA damage, autophagy, and accelerated follicular atresia. Furthermore, we noticed genes participating in extracellular matrix organisation, integrin and gap junction signalling, essential for structural support of the ovarian stroma were profoundly altered. CONCLUSIONS Our findings provide molecular insights into the dysregulated cellular signalling pathways essential for primordial follicle growth and survival that can explain the etiology of POI in CG patients. This study has implications in the development of future therapeutic interventions to preserve ovarian function and promote female reproductive health. HIGHLIGHTS Created a comprehensive single-nucleus transcriptomic atlas and spatial landscape of paediatric ovary tissue from prepubertal girls diagnosed with classic galactosemia (CG). Our transcriptomic analysis revealed activation of genes associated with ER-stress signalling, oxidative stress response and ATM signalling/DNA damage response as shown by significant increase in expression of p-EIF2A, p-H2A.X and LC3A/B in the primordial follicles of CG ovary. PTEN/PI3K/AKT signalling pathways was dysregulated evidenced by a significant reduction in phospho-AKT expression in the primordial follicles of CG ovary, suggesting impaired follicle activation and survival.
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Affiliation(s)
- Raghuveer Kavarthapu
- Division of Pediatric and Adolescent GynecologyEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaMarylandUSA
| | - Hong Lou
- Division of Pediatric and Adolescent GynecologyEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaMarylandUSA
| | | | - Han Do
- BioTuring IncSan DiegoCaliforniaUSA
| | - Mary E. Soliman
- Division of Pediatric and Adolescent GynecologyEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaMarylandUSA
| | - Taylor Badger
- Division of Pediatric and Adolescent GynecologyEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaMarylandUSA
| | - Ramya Balasubramanian
- Division of Pediatric and Adolescent GynecologyEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaMarylandUSA
| | - Victoria Huyhn
- Division of Pediatric and Adolescent GynecologyEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaMarylandUSA
| | - Maria De La Luz Sierra
- Division of Pediatric and Adolescent GynecologyEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaMarylandUSA
| | - Jacqueline C. Yano Maher
- Division of Pediatric and Adolescent GynecologyEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaMarylandUSA
- Division of Pediatric and Adolescent GynecologyChildren's National HospitalWashingtonDistrict of ColumbiaUSA
| | - Veronica Gomez‐Lobo
- Division of Pediatric and Adolescent GynecologyEunice Kennedy Shriver National Institute of Child Health and Human DevelopmentBethesdaMarylandUSA
- Division of Pediatric and Adolescent GynecologyChildren's National HospitalWashingtonDistrict of ColumbiaUSA
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Beilankouhi EAV, Maghsoodi MS, Sani MZ, Khosroshahi NS, Zarezadeh R, Nargesi MM, Safaralizadeh R, Valilo M. miRNAs that regulate apoptosis in breast cancer and cervical cancer. Cell Biochem Biophys 2024; 82:1993-2006. [PMID: 38969951 DOI: 10.1007/s12013-024-01405-7] [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] [Accepted: 07/03/2024] [Indexed: 07/07/2024]
Abstract
In today's world, one of the main problems is cancer, which still has a long way to go to cure it, and it brings a lot of financial and emotional costs to the people of society and governments. Breast cancer (BC) and cervical cancer (CC), two of the most common cancers, are caused by several genetic and environmental factors in women. These two cancers' involvement rate is higher than other cancers in women. microRNAs (miRNAs) are non-coding RNA molecules with a length of 18 to 24 nucleotides, which play an important role in post-translational changes. miRNAs themselves are divided into two categories, oncomiRs and tumor suppressors. OncomiRs have a part in tumor expansion and tumor suppressors prevent tumor development and progress. miRNAs can control cellular processes by regulating various pathways including autophagy, apoptosis, and signaling. Apoptosis is a type of programmed cell death that includes intrinsic and extrinsic pathways and is different from other cell death pathways such as necrosis and ferroptosis. Apoptosis controls the growth, differentiation, and death of cells by regulating the death of damaged and old cells, and since miRNAs are one of the factors that regulate apoptosis, and divided into two categories: pro-apoptotic and anti-apoptotic. We decided in this study to investigate the relationship between miRNAs and apoptosis in the most common women's cancers, BC and CC.
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Affiliation(s)
| | - Maral Salek Maghsoodi
- Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - Maryam Zamani Sani
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Negin Sadi Khosroshahi
- Department of Biology, Faculty of Basic Sciences, Azarbaijan Shahid Madani University, Tabriz, Iran
| | - Reza Zarezadeh
- Department of Clinical Biochemistry and Laboratory Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mirsaed Miri Nargesi
- Molecular Virology and Covid Unit, LabPlus, Department of Pathology and Laboratory Medicine, Auckland City Hospital, Te Whatu Ora Health New Zealand, Auckland, New Zealand
| | - Reza Safaralizadeh
- Department of Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | - Mohammad Valilo
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
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Kaul S, Nair V, Gcanga L, Lakshmanan V, Kalamuddin M, Anang V, Rathore S, Dhawan S, Alam T, Khanna V, Lohiya S, Ali S, Mannan S, Rade K, Parihar SP, Khanna A, Malhotra P, Brombacher F, Dasaradhi PV, Guler R, Mohmmed A. Identifying quantitative sncRNAs signature using global sequencing as a potential biomarker for tuberculosis diagnosis and their role in regulating host response. Int J Biol Macromol 2024; 271:132714. [PMID: 38815937 DOI: 10.1016/j.ijbiomac.2024.132714] [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: 01/10/2024] [Revised: 05/21/2024] [Accepted: 05/27/2024] [Indexed: 06/01/2024]
Abstract
OBJECTIVES The study aimed to identify a quantitative signature of circulating small non-coding RNAs (sncRNAs) as a biomarker for pulmonary tuberculosis disease (active-TB/ATB) and explore their regulatory roles in host-pathogen interactions and disease progression. METHODS We conducted a cross-sectional study recruiting subjects diagnosed with active-TB (drug-sensitive and drug-resistant) and healthy controls. Sera samples were collected and utilized for preparing small RNA libraries. Quantitative patterns of circulating sncRNAs (miRNAs, piRNAs and tRFs) were identified via high-throughput sequencing and DeSeq2 analysis and validated in independent active-TB cohorts. Functional knockdown for two selected miRNAs were also performed. RESULTS A diagnostic signature of four sncRNAs for both drug-sensitive and drug-resistant active-TB cases was validated, exhibiting an AUC of 0.96 (95% CI: 0.937-0.996, p < 0.001) with 86.7% sensitivity (95% CI: 0.775-0.932) and 91.7% specificity (95% CI: 0.730-0.990) in ROC analysis. Functional knockdown demonstrated regulatory roles of hsa-miR-223-5p and hsa-miR-10b-5p in Mycobacterium tuberculosis (Mtb) growth and pro-inflammatory cytokine expression (IL-6 and IL-8). CONCLUSION The study identified a diagnostic tool utilizing a signature of four sncRNAs with high specificity and sensitivity, enhancing our understanding of sncRNAs as ATB diagnostic biomarker. Additionally, hsa-miR-223-5p and hsa-miR-10b-5p demonstrated potential roles in Mtb pathogenesis and host-response to infection.
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Affiliation(s)
- Sheetal Kaul
- International Centre for Genetic Engineering and Biotechnology, New Delhi, India; Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | - Vivek Nair
- International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Lorna Gcanga
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa; Division of Immunology, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine (IDM), Immunology of Infectious Diseases, Faculty of Health Sciences, South African Medical Research Council (SAMRC), University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | | | - M Kalamuddin
- International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Vandana Anang
- International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Sumit Rathore
- All India Institute of Medical Sciences, New Delhi, India
| | - Shikha Dhawan
- International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Tanvir Alam
- College of Science and Engineering, Hamad Bin Khalifa University, Doha 34110, Qatar
| | - Vishal Khanna
- Chest Clinic (Tuberculosis), Lok Nayak Hospital, New Delhi, India
| | - Sheelu Lohiya
- Chest Clinic (Tuberculosis), Lok Nayak Hospital, New Delhi, India
| | - Shakir Ali
- Department of Biochemistry, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India
| | | | | | - Suraj P Parihar
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Ashwani Khanna
- Chest Clinic (Tuberculosis), Lok Nayak Hospital, New Delhi, India
| | - Pawan Malhotra
- International Centre for Genetic Engineering and Biotechnology, New Delhi, India
| | - Frank Brombacher
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa; Division of Immunology, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine (IDM), Immunology of Infectious Diseases, Faculty of Health Sciences, South African Medical Research Council (SAMRC), University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | | | - Reto Guler
- International Centre for Genetic Engineering and Biotechnology, Cape Town Component, Cape Town, South Africa; Division of Immunology, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine (IDM), Immunology of Infectious Diseases, Faculty of Health Sciences, South African Medical Research Council (SAMRC), University of Cape Town, Cape Town, South Africa; Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Asif Mohmmed
- International Centre for Genetic Engineering and Biotechnology, New Delhi, India.
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Li M, Zhuang L, Jiang T, Sun L. Exosomal miR-223 promotes ARDS by targeting insulin-like growth factor 1 receptor: A cell communication study. Exp Lung Res 2024; 50:42-52. [PMID: 38425288 DOI: 10.1080/01902148.2024.2318561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 02/09/2024] [Indexed: 03/02/2024]
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is a respiratory failure syndrome characterized by hypoxemia and changes in the respiratory system. ARDS is the most common cause of death in COVID-19 deaths was ARDS. In this study, we explored the role of miR-223 in exosomes in ARDS. METHODS Exosomes were purified from the supernatants of macrophages. qPCR was used to detect relative mRNA levels. A luciferase reporter assay was performed to verify the miRNA target genes. Western blotting was used to detect the activation of inflammatory pathways. Flow cytometry was performed to assess apoptosis. An LPS-induced ARDS mouse model was used to assess the function of miR-223 in ARDS. RESULTS Exosomes secreted by macrophages promoted apoptosis in A549 cells. Macrophages and exosomes contain high levels of miR-223. Exogenous miR-223 can decrease the expression of insulin-like growth factor 1 receptor (IGF-1R) in A549 and promote the apoptosis of A549.Transfection of anti-miR223 antisense nucleotides effectively reduced the level of miR-223 in macrophages and exosomes and eliminated the pro-apoptotic effect of A549. In vivo, LPS stimulation increased inflammatory cell infiltration in the lungs of mice, whereas knockdown of miR-223 in mice resulted in significantly reduced eosinophil infiltration. CONCLUSIONS Macrophages can secrete exosomes containing miR-223 and promote apoptosis by targeting the IGF-1R/Akt/mTOR signaling pathway in A549 cells and mouse models, suggesting that miR-223 is a potential target for treating COVID-19 induced ARDS.
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Affiliation(s)
- Miaomiao Li
- Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Lilei Zhuang
- Department of Gastroenterology, Yiwu Central Hospital, The Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu, China
| | - Tao Jiang
- Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Li Sun
- Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, China
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8
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Sahin Y, Altan Z, Karabulut A, Saadat KASM, Arslan A. The role of miR-223 in breast cancer; an integrated analysis. Mol Biol Rep 2023; 50:10179-10188. [PMID: 37924447 DOI: 10.1007/s11033-023-08850-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/26/2023] [Indexed: 11/06/2023]
Abstract
BACKGROUND Breast cancer (BRCA) is the most common and leading cause of cancer-related death in women. MicroRNAs (miRNAs) are short non-coding RNA fragments that play a role in regulating gene expression including the cancer-related pathways. Although dysregulation of miR-223 has been demonstrated in recent studies to have prognostic value in various cancers, its diagnostic and prognostic role in BRCA remains unknown. METHODS The expression and the prognostic value of miR-223 were evaluated using the TCGA data and verified by qRT-PCR. Subsequently, potential oncogenic targets of miR-223 were identified by using three different miRNA target prediction tools and the GEPIA database. In addition to these databases, protein-protein interaction network, molecular functions, prognostic value, and the expression level of miR-223 targets were included by using several other bioinformatics tools and databases; such as, UALCAN, GeneMANIA and Metascape. RESULTS The bioinformatic results demonstrated that miR-223 downregulated in BRCA and associated with poor prognosis of patients. In vitro experiments validated that miR-223 significantly downregulated in BRCA cells, MCF-7, SK-BR3, MDA-MB-231 and HCC1500, compared to normal breast cell line hTERT-HME1. Furthermore, ANLN, DYNLT1, LRRC59, SLC12A8 and TPM3 genes were identified as the potential oncogenic target genes of miR-223 based on their expression and prognosis in BRCA. Additionally, protein-protein interaction network of these target genes was mainly enriched in dynein intermediate chain binding, cell division, regulation of cell cycle process, and positive regulation of cellular component biogenesis. CONCLUSIONS The results suggests that miR-223 and its targets, ANLN, DYNLT1, LRRC59, SLC12A8 and TPM3, might be reliable potential prognostic biomarkers in BRCA patients.
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Affiliation(s)
- Yunus Sahin
- Department of Medical Biology, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Zekiye Altan
- Department of Medical Biology, Faculty of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Aydın Karabulut
- Department of Immunology, Institute of Health Sciences, Health Sciences University, Mekteb-i Tıbbiye-i Sahane (Hamidiye) Kulliyesi, Uskudar, İstanbul, Turkey
| | - Khandakar A S M Saadat
- Department of Medical Biology, Faculty of Medicine, Institute of Health Sciences, Gaziantep University, Gaziantep, Turkey
| | - Ahmet Arslan
- Department of Medical Genetics, Faculty of Medicine, Research and Application Hospital, Tekirdag Namık Kemal University, Suleymanpasa, Tekirdag, Turkey.
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9
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Amiri BS, Sabernia N, Abouali B, Amini P, Rezaeeyan H. Evaluation of MicroRNA as Minimal Residual Disease in Leukemia: Diagnostic and Prognostic Approach: A Review. IRANIAN JOURNAL OF PUBLIC HEALTH 2023; 52:2541-2553. [PMID: 38435763 PMCID: PMC10903317 DOI: 10.18502/ijph.v52i12.14315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 05/19/2023] [Indexed: 03/05/2024]
Abstract
Various factors are effective in the development of minimal residual disease (MRD), one of which is MicroRNAs (miRNAs). miRNAs and their dysfunction in gene expression have influential role in the pathogenesis of leukemia. Nowadays, treatments that lead to the suppression or replacement of miRNAs have been developed. Focusing on the role of miRNAs in managing the treatment of leukemia, in this review article we have investigated the miRNAs and signaling pathways involved in the process of apoptosis and cell proliferation, as well as miRNAs with oncogenic function in malignant leukemia cells. Among the studied miRNAs, miR-99a, and miR-181a play an essential role in apoptosis, proliferation and oncogenesis via AKT, MAPK, RAS, and mTOR signaling pathways. miR-223 and miR-125a affect apoptosis and oncogenesis via Wnt/B-catenin, PTEN/PI3K, and STAT5/AKT/ERK/Src signaling pathways. miR-100 also affects both apoptosis and oncogenesis; it acts via IGF1 and mTOR signaling pathways.
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Affiliation(s)
- Bahareh Shateri Amiri
- Department of Internal Medicine, School of Medicine, Hazrat-e Rasool General Hospital, Iran University of Medical Sciences Tehran, Iran
| | - Neda Sabernia
- Department of Internal Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Behdokht Abouali
- Department of Ophthalmology, School of Medicine, Infectious Ophthalmologic Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Parya Amini
- Department of Cardiology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hadi Rezaeeyan
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Iranian Blood Transfusion Organization, Tehran, Iran
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10
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Singh P. MicroRNA based combinatorial therapy against TKIs resistant CML by inactivating the PI3K/Akt/mTOR pathway: a review. Med Oncol 2023; 40:300. [PMID: 37713129 DOI: 10.1007/s12032-023-02161-z] [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: 06/05/2023] [Accepted: 08/14/2023] [Indexed: 09/16/2023]
Abstract
Chronic myeloid leukemia (CML) is characterized by presence of Philadelphia chromosome, which harbors BCR-ABL oncogene responsible for encoding BCR-ABL oncoprotein. This oncoprotein interferes with cellular signaling pathways, resulting in tumor progression. Among these pathways, PI3K/Akt/mTOR pathway is significantly upregulated in CML. Tyrosine kinase inhibitors (TKIs) are current standard therapy for CML, and they have shown remarkable efficacy. However, emergence of TKIs drug resistance has necessitated investigation of novel therapeutic approaches. Components of PI3K/Akt/mTOR pathway have emerged as attractive targets in this context, as this pathway is known to be activated in TKIs-resistant CML cells/patients. Inhibiting this pathway may provide a complementary approach to improving TKIs' efficacy and treatment outcomes. Given previous research indicating that miRNAs play an inhibitory role in cancer, current study used computational tools to identify miRNAs that specifically target pathway's core components. A comprehensive analysis was performed, resulting in identification of 111 miRNAs that potentially target PI3K/Akt/mTOR pathway. From this extensive list, 7 miRNAs was selected for further investigation based on their consistent downregulation across leukemia subtypes. Except for hsa-miR-199a-3p, remaining six miRNAs have been extensively studied in acute myeloid leukemia (AML). Given high similarity between AML and CML, it is believed that six miRNAs which are not studied in context of CML may also be advantageous for curing chemoresistance in CML. Building upon this knowledge, it is reasonable to speculate that a combination therapy approach involving use of miRNAs alongside TKIs may offer improved therapy for TKIs-resistant CML compared to TKIs monotherapy alone.
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Affiliation(s)
- Priyanka Singh
- Department of Biochemistry, School of Basic Sciences, Central University of Punjab, Ghudda, 151401, Bathinda, India.
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11
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Derks B, Rivera-Cruz G, Hagen-Lillevik S, Vos EN, Demirbas D, Lai K, Treacy EP, Levy HL, Wilkins-Haug LE, Rubio-Gozalbo ME, Berry GT. The hypergonadotropic hypogonadism conundrum of classic galactosemia. Hum Reprod Update 2023; 29:246-258. [PMID: 36512573 PMCID: PMC9976963 DOI: 10.1093/humupd/dmac041] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 11/19/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Hypergonadotropic hypogonadism is a burdensome complication of classic galactosemia (CG), an inborn error of galactose metabolism that invariably affects female patients. Since its recognition in 1979, data have become available regarding the clinical spectrum, and the impact on fertility. Many women have been counseled for infertility and the majority never try to conceive, yet spontaneous pregnancies can occur. Onset and mechanism of damage have not been elucidated, yet new insights at the molecular level are becoming available that might greatly benefit our understanding. Fertility preservation options have expanded, and treatments to mitigate this complication either by directly rescuing the metabolic defect or by influencing the cascade of events are being explored. OBJECTIVE AND RATIONALE The aims are to review: the clinical picture and the need to revisit the counseling paradigm; insights into the onset and mechanism of damage at the molecular level; and current treatments to mitigate ovarian damage. SEARCH METHODS In addition to the work on this topic by the authors, the PubMed database has been used to search for peer-reviewed articles and reviews using the following terms: 'classic galactosemia', 'gonadal damage', 'primary ovarian insufficiency', 'fertility', 'animal models' and 'fertility preservation' in combination with other keywords related to the subject area. All relevant publications until August 2022 have been critically evaluated and reviewed. OUTCOMES A diagnosis of premature ovarian insufficiency (POI) results in a significant psychological burden with a high incidence of depression and anxiety that urges adequate counseling at an early stage, appropriate treatment and timely discussion of fertility preservation options. The cause of POI in CG is unknown, but evidence exists of dysregulation in pathways crucial for folliculogenesis such as phosphatidylinositol 3-kinase/protein kinase B, inositol pathway, mitogen-activated protein kinase, insulin-like growth factor-1 and transforming growth factor-beta signaling. Recent findings from the GalT gene-trapped (GalTKO) mouse model suggest that early molecular changes in 1-month-old ovaries elicit an accelerated growth activation and burnout of primordial follicles, resembling the progressive ovarian failure seen in patients. Although data on safety and efficacy outcomes are still limited, ovarian tissue cryopreservation can be a fertility preservation option. Treatments to overcome the genetic defect, for example nucleic acid therapy such as mRNA or gene therapy, or that influence the cascade of events are being explored at the (pre-)clinical level. WIDER IMPLICATIONS Elucidation of the molecular pathways underlying POI of any origin can greatly advance our insight into the pathogenesis and open new treatment avenues. Alterations in these molecular pathways might serve as markers of disease progression and efficiency of new treatment options.
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Affiliation(s)
- Britt Derks
- Department of Pediatrics and Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands.,GROW, Maastricht University, Maastricht, The Netherlands.,European Reference Network for Hereditary Metabolic Disorders (MetabERN) Member and United for Metabolic Diseases Member
| | - Greysha Rivera-Cruz
- Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Synneva Hagen-Lillevik
- Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.,Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT, USA
| | - E Naomi Vos
- Department of Pediatrics and Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands.,GROW, Maastricht University, Maastricht, The Netherlands.,European Reference Network for Hereditary Metabolic Disorders (MetabERN) Member and United for Metabolic Diseases Member
| | - Didem Demirbas
- Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kent Lai
- Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.,Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT, USA
| | - Eileen P Treacy
- European Reference Network for Hereditary Metabolic Disorders (MetabERN) Member and United for Metabolic Diseases Member.,National Centre for Inherited Metabolic Disorders, Mater Misericordiae University Hospital, Dublin, Ireland.,School of Medicine, Trinity College, Dublin 2, Ireland.,School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
| | - Harvey L Levy
- Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Louise E Wilkins-Haug
- Division of Maternal Fetal Medicine, Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - M Estela Rubio-Gozalbo
- Department of Pediatrics and Clinical Genetics, Maastricht University Medical Centre+, Maastricht, The Netherlands.,GROW, Maastricht University, Maastricht, The Netherlands.,European Reference Network for Hereditary Metabolic Disorders (MetabERN) Member and United for Metabolic Diseases Member
| | - Gerard T Berry
- Division of Genetics & Genomics, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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12
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Relevance of miR-223 as Potential Diagnostic and Prognostic Markers in Cancer. BIOLOGY 2022; 11:biology11020249. [PMID: 35205115 PMCID: PMC8869096 DOI: 10.3390/biology11020249] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/31/2022] [Accepted: 02/03/2022] [Indexed: 12/21/2022]
Abstract
In 1993, the discovery of microRNAs in Caenorhabditis elegans (C. elegans) altered the paradigmatic view of RNA biology and post-transcriptional gene regulation. Further study revealed the role of microRNAs in disease development and progression. In particular, this review highlights microRNA-223 (miR-223 or miRNA-223) expression in malignant neoplastic disorders. miR-223 expression controls aspects of hematopoiesis and apoptosis, and cell proliferation, migration, and invasion. miR-223 regulates a number of gene targets, including cytoplasmic activation/proliferation-associated protein-1 (Caprin-1), insulin-like growth factor-1 receptor (IGF-1R), and other cell proliferation- and cell cycle-associated genes. Several studies have proposed miR-223 as a novel biomarker for early cancer diagnosis. Here, we emphasize miR-223′s role in the development and progression of cancer.
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13
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Kashani B, Zandi Z, Kaveh V, Pourbagheri-Sigaroodi A, Ghaffari SH, Bashash D. Small molecules with huge impacts: the role of miRNA-regulated PI3K pathway in human malignancies. Mol Biol Rep 2021; 48:8045-8059. [PMID: 34689281 DOI: 10.1007/s11033-021-06739-6] [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: 04/28/2021] [Accepted: 09/15/2021] [Indexed: 11/28/2022]
Abstract
Along with evolution, a considerable number of signaling cascades have evolved within cells to meet their multifaceted needs. Among transmitting molecules, phosphoinositide 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) have teamed up to build a signaling axis that effectively regulates various cellular processes including cell proliferation and migration. Given the extensive output of the PI3K/Akt/mTOR signaling axis, its aberrancy could subsequently lead to the formation of a wide range of human cancers spanning from hematologic malignancies to different types of solid tumors. Despite the high frequency of the PI3K pathway over-activation in most malignancies, mutations in the DNA sequence are not equally common. Such incompatibility sheds light on the possible effects of post-translational modification mechanisms that may take control of this pathway, some of the most important ones of which are through microRNAs (miRNAs or miRs). The present review is designed to take off the veil from the regulatory role of these small non-coding RNAs on the PI3K/Akt/mTOR signaling axis in carcinogenesis.
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Affiliation(s)
- Bahareh Kashani
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Zandi
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Kaveh
- Department of Medical Oncology and Hematology, Iran University of Medical Sciences, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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14
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Kalushkova A, Nylund P, Párraga AA, Lennartsson A, Jernberg-Wiklund H. One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies. EPIGENOMES 2021; 5:epigenomes5040022. [PMID: 34968247 PMCID: PMC8715477 DOI: 10.3390/epigenomes5040022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/17/2021] [Accepted: 09/26/2021] [Indexed: 02/01/2023] Open
Abstract
Aberrant DNA methylation, dysregulation of chromatin-modifying enzymes, and microRNAs (miRNAs) play a crucial role in haematological malignancies. These epimutations, with an impact on chromatin accessibility and transcriptional output, are often associated with genomic instability and the emergence of drug resistance, disease progression, and poor survival. In order to exert their functions, epigenetic enzymes utilize cellular metabolites as co-factors and are highly dependent on their availability. By affecting the expression of metabolic enzymes, epigenetic modifiers may aid the generation of metabolite signatures that could be utilized as targets and biomarkers in cancer. This interdependency remains often neglected and poorly represented in studies, despite well-established methods to study the cellular metabolome. This review critically summarizes the current knowledge in the field to provide an integral picture of the interplay between epigenomic alterations and the cellular metabolome in haematological malignancies. Our recent findings defining a distinct metabolic signature upon response to enhancer of zeste homolog 2 (EZH2) inhibition in multiple myeloma (MM) highlight how a shift of preferred metabolic pathways may potentiate novel treatments. The suggested link between the epigenome and the metabolome in haematopoietic tumours holds promise for the use of metabolic signatures as possible biomarkers of response to treatment.
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Affiliation(s)
- Antonia Kalushkova
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden; (P.N.); (A.A.P.); (H.J.-W.)
- Correspondence:
| | - Patrick Nylund
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden; (P.N.); (A.A.P.); (H.J.-W.)
| | - Alba Atienza Párraga
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden; (P.N.); (A.A.P.); (H.J.-W.)
| | - Andreas Lennartsson
- Department of Biosciences and Nutrition, NEO, Karolinska Institutet, 14157 Huddinge, Sweden;
| | - Helena Jernberg-Wiklund
- Science for Life Laboratory, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 75185 Uppsala, Sweden; (P.N.); (A.A.P.); (H.J.-W.)
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15
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Alterations in microRNA Expression during Hematopoietic Stem Cell Mobilization. BIOLOGY 2021; 10:biology10070668. [PMID: 34356523 PMCID: PMC8301406 DOI: 10.3390/biology10070668] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 01/01/2023]
Abstract
Simple Summary Lymphoproliferative disorders comprise a heterogeneous group of hematological malignancies characterized by abnormal lymphocyte proliferation. Autologous hematopoietic stem cell transplantation plays a very important role in the treatment of lymphoproliferative diseases. The key element in this process is the effective mobilization of hematopoietic cells from the marrow niche to the peripheral blood. Mobilization of HSC is regulated by many factors, out of which miRNAs present in the hematopoietic niche via targeting cytokines, and signaling pathways may play an important regulatory role. This study investigated the expression of selected miRNAs in patients with multiple myeloma, Hodgkin’s lymphomas, and non-Hodgkin’s lymphomas undergoing mobilization procedures. The aim of the study was to evaluate the expression of hsa-miR-15a-5p, hsa-miR-16-5p, hsa-miR-34a-5p, hsa-miR-126-3p, hsa-miR-146a-5p, hsa-miR-155-5p, and hsa-miR-223-3p during the mobilization procedure, and to assess their role in mobilization efficacy. The level of miRNAs was tested at two time points before the initiation of mobilization and on the day of the first apheresis. Our results suggest that the investigated miRNAs, especially hsa-miR-146a-5p, may influence the efficacy of HSC mobilization. Abstract microRNAs play an important role in the regulation of gene expression, cell fate, hematopoiesis, and may influence the efficacy of CD34+ cell mobilization. The present study examines the role of hsa-miR-15a-5p, hsa-miR-16-5p, hsa-miR-34a-5p, hsa-miR-126-3p, hsa-miR-146a-5p, hsa-miR-155-5p, and hsa-miR-223-3p in the course of hematopoietic stem cell mobilization. The numbers of CD34+ cells collected in patients with hematological malignancies (39 multiple myelomas, 11 lymphomas) were determined during mobilization for an autologous hematopoietic stem cell transplantation. The miRNA level was evaluated by RT-PCR. Compared to baseline, a significant decline in hsa-miR-15a-5p, hsa-miR-16-5p, hsa-miR-126-3p, hsa-miR-146a-5p, and hsa-miR-155-5p was observed on the day of the first apheresis (day A). An increase was observed only in the expression of hsa-miR-34a-5p. On day A, a negative correlation was found between hsa-miR-15a-5p and hsa-miR-146a-5p levels and the number of CD34+ cells in peripheral blood. A negative correlation was observed between hsa-miR-146a-5p and the number of collected CD34+ cells after the first apheresis. Good mobilizers, defined according to GITMO criteria, demonstrated a lower hsa-miR-146a-5p level on day A than poor mobilizers. Patients from the hsa-miR-146a-5p “low expressors” collected more CD34+ cells than “high expressors”. Our results suggest that the investigated miRNAs, especially hsa-miR-146a-5p, may influence the efficacy of HSC mobilization.
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16
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Zhang Y, Xiang D, Hu X, Ruan Q, Wang L, Bao Z. Identification and study of differentially expressed miRNAs in aged NAFLD rats based on high-throughput sequencing. Ann Hepatol 2021; 19:302-312. [PMID: 31899128 DOI: 10.1016/j.aohep.2019.12.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 11/29/2019] [Accepted: 12/04/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Hepatic microRNA (miR) expression profiles were explored in aged rats with NAFLD, in order to clarify the molecular mechanisms underlying the pathophysiological processes of aging-related NAFLD. PATIENTS OR MATERIALS AND METHODS 24 aged rats (18-month-old) and 24 young rats (2-month-old) were randomly divided into two subgroups according to diet, control group and NAFLD group. After 8 weeks of administering 45% high-fat diet or normal diet, total hepatic RNA was extracted from liver tissues of the aged rats. Differentially expressed microRNAs (DE-miRs) in aged NAFLD group were detected and screened out using high-throughput sequencing technology. The data were subjected to Gene Ontology functional enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses using a bioinformatics approach. The sequencing results were further verified by RT-qPCR. RESULTS Compared with the aged control liver tissues, 6 significantly upregulated miRs (miR-881-3p, miR-871-3p, miR-335, miR-223-3p, miR-155-5p, miR-146b-5p) and 4 significantly downregulated miRs (miR-182, miR-193-3p, miR-31a-5p and miR-96-5p) were identified in the aged NAFLD liver tissues. These DE-miRs were found to be involved in the regulation of cell signaling transduction and metabolism processes, probably affecting signaling pathways relevant to insulin secretion and some senile diseases. RT-qPCR results corroborated the sequencing results and demonstrated that 6 significantly upregulated miRs were not identified in the young group. CONCLUSIONS A total of 10 DE-miRs identified in the aged NAFLD rats were involved in some certain insulin secretion and age-related functional pathways, which may serve as novel candidate targets for the diagnosis and treatment of aging-associated NAFLD.
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Affiliation(s)
- Ying Zhang
- Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Danni Xiang
- Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China
| | - Xiaona Hu
- Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Qingwei Ruan
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Lina Wang
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, China
| | - Zhijun Bao
- Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital, Fudan University, Shanghai, China.
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17
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Asl ER, Amini M, Najafi S, Mansoori B, Mokhtarzadeh A, Mohammadi A, Lotfinejad P, Bagheri M, Shirjang S, Lotfi Z, Rasmi Y, Baradaran B. Interplay between MAPK/ERK signaling pathway and MicroRNAs: A crucial mechanism regulating cancer cell metabolism and tumor progression. Life Sci 2021; 278:119499. [PMID: 33865878 DOI: 10.1016/j.lfs.2021.119499] [Citation(s) in RCA: 130] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 03/29/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023]
Abstract
Mitogen-activated protein kinase (MAPK) signal transduction, as a highly conserved signaling pathway, is reported to be involved in various biological events, including metabolic reprogramming, cell proliferation, survival, and differentiation. Mutations in key molecules involved in MAPK/ERK signaling and dysregulation of this pathway are very common events in various human malignancies, which make the MAPK signaling a crucial signaling pathway participating in the regulation of glucose uptake by malignant cells and tumorigenesis. MicroRNAs (miRNAs), as small non-coding RNAs, are critical regulators of gene expression that play key roles in cancer initiation and progression. On the other hand, these small RNAs mutually regulate the MAPK signaling which is often overexpressed in the case of cancer progression; suggesting that crosstalk between miRNAs and this signaling pathway plays a pivotal role in the development of human cancers. Some miRNAs such as miR-20b, miR-34c-3p, miR-152, miR-181a, and miR-302b through inhibiting MAPK signaling, and miR-193a-3p, miR-330-3p, and miR-592 by activating this signaling pathway, play imperative roles in tumorigenesis. Therefore, in this review, we aimed to focus on the interplay between miRNAs and MAPK signaling in the various steps of tumorigenesis, including metabolic regulation, cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance.
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Affiliation(s)
- Elmira Roshani Asl
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.; Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Mohammadi
- Department of Cancer and Inflammation Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Parisa Lotfinejad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences
| | - Mehdi Bagheri
- Department of Biology, Khorasan Razavi Science and Research Branch, Islamic Azad University, Neyshabur, Iran
| | - Solmaz Shirjang
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ziba Lotfi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yousef Rasmi
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.; Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran..
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran..
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Zhang Y, Li Y, Wang Q, Su B, Xu H, Sun Y, Sun P, Li R, Peng X, Cai J. Role of RASA1 in cancer: A review and update (Review). Oncol Rep 2020; 44:2386-2396. [PMID: 33125148 PMCID: PMC7610306 DOI: 10.3892/or.2020.7807] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 09/22/2020] [Indexed: 12/24/2022] Open
Abstract
Ras p21 protein activator 1 (RASA1) is a regulator of Ras GDP and GTP and is involved in numerous physiological processes such as angiogenesis, cell proliferation, and apoptosis. As a result, RASA1 also contributes to pathological processes in vascular diseases and tumour formation. This review focuses on the role of RASA1 in multiple tumours types in the lung, intestines, liver, and breast. Furthermore, we discuss the potential mechanisms of RASA1 and its downstream effects through Ras/RAF/MEK/ERK or Ras/PI3K/AKT signalling. Moreover, miRNAs are capable of regulating RASA1 and could be a novel targeted treatment strategy for tumours.
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Affiliation(s)
- Yanhua Zhang
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Yue Li
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Quanyue Wang
- Qinghai Institute of Health Sciences, Xining, Qinghai 810000, P.R. China
| | - Bo Su
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
- Department of Pathology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Hui Xu
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Yang Sun
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Pei Sun
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Rumeng Li
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Xiaochun Peng
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
- Department of Pathophysiology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Jun Cai
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434023, P.R. China
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Collison AM, Sokulsky LA, Nightingale S, Percival E, LeFevre A, Meredith J, Krauss S, Foster PS, Mattes J. In vivo targeting of miR-223 in experimental eosinophilic oesophagitis. Clin Transl Immunology 2020; 9:e1210. [PMID: 33282292 PMCID: PMC7683276 DOI: 10.1002/cti2.1210] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 08/19/2020] [Accepted: 10/20/2020] [Indexed: 01/03/2023] Open
Abstract
Objectives Eosinophilic oesophagitis (EoE) is characterised by oesophageal inflammation, fibrosis and dysfunction. Micro (mi)-RNAs interfere with pro-inflammatory and pro-fibrotic transcriptional programs, and miR-223 was upregulated in oesophageal mucosal biopsy specimens from EoE patients. The therapeutic potential of modulating miR-223 expression in vivo has not been determined. We aimed to elucidate the relevance of oesophageal miR-223 expression in an in vivo model of EoE by inhibiting miR-223 tissue expression. Methods The expression of miR-223 and the validated miR-223 target insulin-like growth factor receptor 1 (IGF1R) protein was determined in our paediatric cohort of EoE patients. A murine model of Aspergillus fumigatus-induced EoE was employed, and oesophagi were assessed for miR-233, IGF1R, T lymphocyte type 2 (T2) cytokine expression and eosinophil infiltration. Mice were treated with antagomirs targeting miR-223 or resveratrol targeting its upstream regulator Midline-1(MID-1). Results There was an inverse relationship between an increased expression of miR-223 and a decreased IGF1R protein concentration in biopsy specimens from EoE patients. TNF-related apoptosis-inducing ligand deficiency, MID-1 inhibition and resveratrol treatment suppressed miR-223 expression. Furthermore, inhibition of miR-223 and treatment with resveratrol in the oesophagus resulted in an amelioration of EoE hallmark features including eosinophilic infiltration, oesophageal circumference and a reduction in T2 cytokine expression. Conclusion miR-223 has a key role in the perpetuation of EoE hallmark features downstream of TNF-related apoptosis-inducing ligand and MID-1 in an experimental model. These studies highlight a potentially critical role of miRNA function in EoE aetiology. miR-223 expression in the oesophagus may be therapeutically modulated by resveratrol, providing a potential new therapeutic option to be explored in EoE patients for this increasingly prevalent condition.
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Affiliation(s)
- Adam M Collison
- Experimental and Translational Respiratory Medicine Group Newcastle NSW Australia.,Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Leon A Sokulsky
- Experimental and Translational Respiratory Medicine Group Newcastle NSW Australia.,Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia.,Priority Research Centre for Healthy Lungs The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Scott Nightingale
- Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia.,Paediatric Gastroenterology Department John Hunter Children's Hospital Newcastle NSW Australia
| | - Elizabeth Percival
- Experimental and Translational Respiratory Medicine Group Newcastle NSW Australia.,Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Anna LeFevre
- Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Joseph Meredith
- Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Sybille Krauss
- Faculty IV: School of Science and Technology Institute of Biology Department Human Biology/Neurobiology University of Siegen Siegen Germany
| | - Paul S Foster
- Priority Research Centre for Healthy Lungs The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia
| | - Joerg Mattes
- Experimental and Translational Respiratory Medicine Group Newcastle NSW Australia.,Priority Research Centre GrowUpWell The University of Newcastle and Hunter Medical Research Institute Newcastle NSW Australia.,Paediatric Respiratory & Sleep Medicine Department Newcastle Children's Hospital Kaleidoscope Newcastle NSW Australia
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20
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Li C, Zhao T, Nie L, Zou Y, Zhang Q. MicroRNA-223 decreases cell proliferation, migration, invasion, and enhances cell apoptosis in childhood acute lymphoblastic leukemia via targeting Forkhead box O 1. Biosci Rep 2020; 40:BSR20200485. [PMID: 32964916 PMCID: PMC7538682 DOI: 10.1042/bsr20200485] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 09/15/2020] [Accepted: 09/15/2020] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE Acute lymphoblastic leukemia (ALL) is a frequent malignancy in childhood. The present study was aimed to investigate the effect of miR-223 in ALL and its underlying molecular mechanisms. METHODS The mRNA expression of miR-223 and FOXO1 was detected by qRT-RCR in ALL children. The correlation between miR-223 and clinical indexes of ALL was determined. CCRF-CEM and NALM-6 cells were transfected with miR-223 mimic and miR-223 inhibitor, respectively. The proliferation, apoptosis, invasion and migration of CCRF-CEM and NALM-6 cells were measured by MTT, flow cytometry and transwell assay. The protein expression of FOXO1 was detected by Western blot. Additionally, dual-luciferase reporter and RNA pull-down assay were performed to investigate the target gene of miR-223 and validate their targeting relationship. RESULTS The mRNA expression of miR-223 was markedly down-regulated in ALL, but FOXO1 was up-regulated. The protein expression of FOXO1 was highly expressed in CCRF-CEM and NALM-6 cells. The expression of miR-223 was related to WBC, PLT, RBC and risk stratification. Overexpression of miR-223 not only inhibited cell proliferation, migration and invasion, but also induced cell apoptosis. Importantly, FOXO1 was a target gene of miR-223 in ALL cells. Silencing of FOXO1 reversed the effects of miR-223 inhibitor on cell proliferation, migration, invasion and apoptosis in ALL. CONCLUSIONS miR-223 could inhibit cell proliferation, migration and invasion, and promote apoptosis by targeting FOXO1 in ALL.
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Affiliation(s)
- Chunyu Li
- Department of Pediatrics, The First Affiliated Hospital of Jiamusi University, No. 348 dexiang Street, Jiamusi City, Heilongjiang Province 154002, China
| | - Tana Zhao
- Department of Pediatrics, The First Affiliated Hospital of Jiamusi University, No. 348 dexiang Street, Jiamusi City, Heilongjiang Province 154002, China
| | - Lei Nie
- Department of Pediatrics, The First Affiliated Hospital of Jiamusi University, No. 348 dexiang Street, Jiamusi City, Heilongjiang Province 154002, China
| | - Yanhong Zou
- Department of Pediatrics, The First Affiliated Hospital of Jiamusi University, No. 348 dexiang Street, Jiamusi City, Heilongjiang Province 154002, China
| | - Quan Zhang
- Department of Gastroenterology, Jiamusi Central Hospital, No. 256, Zhongshan Street, Xiangyang District, Jiamusi City, Heilongjiang Province 154002, China
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21
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Wu ZM, Luo J, Shi XD, Zhang SX, Zhu XB, Guo J. Icariin alleviates rheumatoid arthritis via regulating miR-223-3p/NLRP3 signalling axis. Autoimmunity 2020; 53:450-458. [PMID: 33084415 DOI: 10.1080/08916934.2020.1836488] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Rheumatoid arthritis (RA) is considered to be a chronic autoimmune disease, pathogenesis of RA is complex and effective treatments for RA is still lacking. Previous studies found that microRNAs (miRNAs) play important roles in the pathogenesis of RA, and miR-223-3p is considered to be one of the possible biomarkers of RA. Recent studies have revealed that icariin alleviates RA in murine models, but the underlying mechanism needs to be further investigated. MiR-223-3p expression levels in fibroblast-like synoviocyte (RA-FLS) and patients with RA were quantified by qRT-PCR, cell proliferation was analyzed by CCK-8 and BrdU assay. Cell apoptosis was assessed by flow cytometry and western blotting. TNF-α, IL-1β and IL-6 concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Dual luminescence-based reporter gene assay was conducted to confirm the possible interaction between miR-223-3p and NLRP3. Icariin inhibits proliferation and inflammation cytokines secretion, promotes apoptosis of RA-FLS cells and upregulated the expression of miR-223-3p. MiR-223-3p targets to 3'-UTR of NRLP3 and regulates its expression. MiR-223-3p inhibitor reversed the effect of icariin on RA-FLS cells function. Additionally, anti-RA activity of icariin was restored by NLRP3 inhibitor MCC950 in miR-223-3p knockdown RA-FLS cells. Icariin inhibits proliferation and inflammation, promotes apoptosis of RA-FLS cells by regulating miR-223-3p/NLRP3 signalling, which may serve as a potential therapeutic target to alleviate RA.
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Affiliation(s)
- Zhi-Ming Wu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, PR China
| | - Jun Luo
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, PR China
| | - Xiao-Dong Shi
- Department of Rheumatology, The Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, PR China
| | - Shao-Xin Zhang
- Department of Science and Education, The Sixth People's Hospital of Jiujiang City, Jiujiang, PR China
| | - Xiao-Bo Zhu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, PR China
| | - Jian Guo
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, PR China
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Wiesel-Motiuk N, Assaraf YG. The key roles of the lysine acetyltransferases KAT6A and KAT6B in physiology and pathology. Drug Resist Updat 2020; 53:100729. [PMID: 33130515 DOI: 10.1016/j.drup.2020.100729] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 08/21/2020] [Accepted: 08/28/2020] [Indexed: 12/14/2022]
Abstract
Histone modifications and more specifically ε-lysine acylations are key epigenetic regulators that control chromatin structure and gene transcription, thereby impacting on various important cellular processes and phenotypes. Furthermore, lysine acetylation of many non-histone proteins is involved in key cellular processes including transcription, DNA damage repair, metabolism, cellular proliferation, mitosis, signal transduction, protein folding, and autophagy. Acetylation affects protein functions through multiple mechanisms including regulation of protein stability, enzymatic activity, subcellular localization, crosstalk with other post-translational modifications as well as regulation of protein-protein and protein-DNA interactions. The paralogous lysine acetyltransferases KAT6A and KAT6B which belong to the MYST family of acetyltransferases, were first discovered approximately 25 years ago. KAT6 acetyltransferases acylate both histone H3 and non-histone proteins. In this respect, KAT6 acetyltransferases play key roles in regulation of transcription, various developmental processes, maintenance of hematopoietic and neural stem cells, regulation of hematopoietic cell differentiation, cell cycle progression as well as mitosis. In the current review, we discuss the physiological functions of the acetyltransferases KAT6A and KAT6B as well as their functions under pathological conditions of aberrant expression, leading to several developmental syndromes and cancer. Importantly, both upregulation and downregulation of KAT6 proteins was shown to play a role in cancer formation, progression, and therapy resistance, suggesting that they can act as oncogenes or tumor suppressors. We also describe reciprocal regulation of expression between KAT6 proteins and several microRNAs as well as their involvement in cancer formation, progression and resistance to therapy.
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Affiliation(s)
- Naama Wiesel-Motiuk
- The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Laboratory, Dept. of Biology, Technion-Israel Institute of Technology, Haifa, 3200003, Israel.
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23
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Zhang J, Jiang M, Qian L, Lin X, Song W, Gao Y, Zhou Y. The STAT3-miR-223-TGFBR3/HMGCS1 axis modulates the progression of cervical carcinoma. Mol Oncol 2020; 14:2313-2331. [PMID: 32491253 PMCID: PMC7463355 DOI: 10.1002/1878-0261.12737] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 05/06/2020] [Accepted: 05/29/2020] [Indexed: 12/18/2022] Open
Abstract
Cervical cancer is induced by persistent infections with high-risk human papillomaviruses (HPVs), which produce the early protein 6 of HPVs (E6)/E7 protein that is involved in cell transformation by interacting with several oncoproteins or tumor suppressors. However, the role of noncoding RNA in mediating the pathogenesis of cervical cancer remains unclear. Here, we report that the novel signal transducer and activator of transcription 3 (STAT3)-microRNA-223-3p (miR-223)-TGFBR3/HMGCS1 axis regulated by the E6 protein controls cervical carcinogenesis. miR-223 was highly expressed in cervical tumor tissues, whereas TGFBR3 or HMGCS1 was significantly downregulated. miR-223 targeted the 3'-UTRs of TGFBR3 and HMGCS1 and suppressed their expression, leading to increased anchorage-independent growth and cervical squamous cell carcinoma (CSCC) tumor growth in vitro and in vivo. The increased expression of miR-223 was mediated by the transcription factor STAT3, whose activity was enhanced by E6 in the context of interleukin (IL)-6 stimulation. In addition, exosomal miR-223 derived from CSCC cells induced IL-6 secretion by monocyte/macrophage in a coculture system in vitro, and IL-6 secretion, in turn, led to enhanced STAT3 activity in CSSC cells, forming a positive feedback loop. Furthermore, modified miR-223 inhibitor effectively suppressed tumor growth in cell line-derived xenograft model, suggesting that miR-223 is a potential promising therapeutic target in CSCC. In conclusion, our results demonstrate that the STAT3-miR-223-HMGCS1/TGFBR3 axis functions as a key signaling pathway in cervical cancer progression and provides a new therapeutic target.
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Affiliation(s)
- Ju Zhang
- Department of Laboratory MedicineThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
| | - Ming Jiang
- School of Life ScienceUniversity of Science and Technology of ChinaHefeiChina
- China‐US (Henan) Hormel Cancer InstituteZhengzhouChina
| | - Lili Qian
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of University of Science & Technology of ChinaAnhui Provincial HospitalHefeiChina
| | - Xiao Lin
- Department of Laboratory MedicineThe First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiChina
| | - Weiguo Song
- Department of Gynaecology and ObstetricsThe Second Hospital of Anhui Medical UniversityHefeiChina
| | - Yunfeng Gao
- China‐US (Henan) Hormel Cancer InstituteZhengzhouChina
| | - Ying Zhou
- Department of Obstetrics and GynecologyThe First Affiliated Hospital of University of Science & Technology of ChinaAnhui Provincial HospitalHefeiChina
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24
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Hao M, Wang H, Zhang C, Li C, Wang X. Minichromosome maintenance protein 5 is an important pathogenic factor of oral squamous cell carcinoma. Oncol Lett 2020; 20:109. [PMID: 32831928 PMCID: PMC7439113 DOI: 10.3892/ol.2020.11970] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Accepted: 07/08/2020] [Indexed: 01/29/2023] Open
Abstract
Oral squamous cell carcinoma is one of the most common causes of malignancy-associated death. Early diagnosis of oral squamous cell carcinoma (OSCC) is important in patient treatment and prognostic evaluation. Due to the lack of significant therapeutic benefit, the 5-year survival rate has not improved. Therefore, effective novel markers are needed to improve diagnosis. To determine novel promising diagnostic biomarkers for OSCC, 416 upregulated and 416 downregulated differentially expressed genes were screened from OSCC tissues using an RNA microarray. The results suggested that minichromosome maintenance protein (MCM5) mRNA was significantly overexpressed in OSCC tissues compared with that in adjacent normal tissues. Moreover, silencing of MCM5 expression an OSCC cell line (SCC-15) significantly impaired proliferation and colony formation. Furthermore, negative regulation of the mRNA and protein expression of MCM5 and demonstrated that MCM5 served as a cancer-promoting gene modulating OSCC cell proliferation through induced G2/M phase arrest. In this process, the mRNA expression of cyclin E and cyclin-dependent kinase 2 was downregulated, while p21 expression was upregulated. These results suggested that MCM5 may be an important pathogenic factor of OSCC. High expression levels of MCM5 may serve as a marker for the early diagnosis of OSCC.
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Affiliation(s)
- Miao Hao
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Huiyu Wang
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Chu Zhang
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Chunyan Li
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
| | - Xiaofeng Wang
- Department of Stomatology, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
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25
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Miao J, Regenstein JM, Xu D, Zhou D, Li H, Zhang H, Li C, Qiu J, Chen X. The roles of microRNA in human cervical cancer. Arch Biochem Biophys 2020; 690:108480. [PMID: 32681832 DOI: 10.1016/j.abb.2020.108480] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 06/19/2020] [Accepted: 06/20/2020] [Indexed: 12/13/2022]
Abstract
Although a potentially preventable disease, cervical cancer (CC) is the second most commonly diagnosed gynaecological cancer with at least 530,000 new cases annually, and the prognosis with CC is still poor. Studies suggest that aberrant expression of microRNA (miRNA) contributes to the progression of CC. As a group of small non-coding RNA with 18-25 nucleotides, miRNA regulate about one-third of all human genes. They function by repressing translation or inducing mRNA cleavage or degradation, including genes involved in diverse and important cellular processes, including cell cycling, proliferation, differentiation, and apoptosis. Results showed that misexpression of miRNA is closely related to the onset and progression of CC. This review will provide an overview of the function of miRNA in CC and the mechanisms involved in cervical carcinogenesis.
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Affiliation(s)
- Jingnan Miao
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Haikou, Hainan, 570100, China; School of Pharmacy, Hainan Medical University, Haikou, Hainan, 570100, China
| | - Joe M Regenstein
- Department of Food Science, Cornell University, Ithaca, NY, 14853-7201, USA
| | - Dan Xu
- School of Pharmacy, Hainan Medical University, Haikou, Hainan, 570100, China
| | - Dan Zhou
- School of Pharmacy, Hainan Medical University, Haikou, Hainan, 570100, China
| | - Haixia Li
- School of Pharmacy, Hainan Medical University, Haikou, Hainan, 570100, China
| | - Hua Zhang
- Department of Food Science, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, Heilongjiang, 150010, China
| | - Chunfeng Li
- Gastrointestinal Surgical Ward, Tumor Hospital of Harbin Medical University, Harbin, Heilongjiang, 150081, China
| | - Junqiang Qiu
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Haikou, Hainan, 570100, China; School of Pharmacy, Hainan Medical University, Haikou, Hainan, 570100, China; Hainan Provincial Key Laboratory of R & D on Tropical Herbs, Haikou, Hainan, 570100, China.
| | - Xun Chen
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Haikou, Hainan, 570100, China; School of Pharmacy, Hainan Medical University, Haikou, Hainan, 570100, China; Hainan Provincial Key Laboratory of R & D on Tropical Herbs, Haikou, Hainan, 570100, China
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Fujii R, Yamada H, Yamazaki M, Munetsuna E, Ando Y, Ohashi K, Ishikawa H, Shimoda H, Sakata K, Ogawa A, Kobayashi S, Suzuki K. Circulating microRNAs (miR-126, miR-197, and miR-223) are associated with chronic kidney disease among elderly survivors of the Great East Japan Earthquake. BMC Nephrol 2019; 20:474. [PMID: 31864304 PMCID: PMC6925484 DOI: 10.1186/s12882-019-1651-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 11/29/2019] [Indexed: 12/18/2022] Open
Abstract
Background A recent study has reported that incidence of chronic kidney disease (CKD) is higher in evacuees, but the molecular mechanism still remains unclear. One plausible hypothesis is a change in vascular function following to psychological distress. In order to assess molecular mechanisms underlying this association, we examined whether cardiovascular disease (CVD)-associated miRNAs (miR-126, miR-197, and miR-223) were associated with CKD among Japanese elderly survivors after an earthquake. Methods We analyzed 1385 individuals (670 men and 715 women) who participated in a post-disaster health check-up after the Great East Japan Earthquake, which occurred in 2011. The check-up involved collection of information about lifestyle, clinical history, the degree of housing damage, and baseline measurement of the estimated glomerular filtration rate. Expression levels of miRNAs were determined using real-time polymerase chain reaction. Estimated glomerular filtration rate (eGFR) was calculated using sex, age, and serum creatinine. CKD was defined as eGFR < 60 ml/min/1.73m2. The multivariable regression analyses were performed to examine the associations between CVD-associated miRNAs and CKD after adjusting potential confounders. Results Mean age (standard deviation) of participants with normal kidney function and CKD was 62.7 (10.6) and 71.9 (8.1) years, respectively. Expression levels of these miRNAs in participants with CKD were significantly lower than normal kidney function (all p < 0.001). Even after adjusting for lifestyle, clinical profiles, and psychological distress, significant associations between three miRNAs and CKD still remained. A significant linear association between the cumulative score of these miRNAs and CKD was found (p = 0.04). Conclusions This cross-sectional study suggested that CVD-associated miRNAs were an important factor of CKD in an elderly Japanese population after earthquake. Future studies need to examine this association in longitudinal dataset.
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Affiliation(s)
- Ryosuke Fujii
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan
| | - Hiroya Yamada
- Department of Hygiene, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan
| | - Mirai Yamazaki
- Department of Clinical Biochemistry, Fujita Health University School of Medical Sciences, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan.,Department of Medical Technology, Kagawa Prefectural University of Health Sciences, 281-1 Hara, Mure-cho, Takamatsu, 761-0123, Japan
| | - Eiji Munetsuna
- Department of Biochemistry, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan
| | - Yoshitaka Ando
- Department of Clinical Biochemistry, Fujita Health University School of Medical Sciences, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan
| | - Koji Ohashi
- Department of Clinical Biochemistry, Fujita Health University School of Medical Sciences, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan
| | - Hiroaki Ishikawa
- Department of Clinical Biochemistry, Fujita Health University School of Medical Sciences, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan
| | - Haruki Shimoda
- Department of Hygiene and Preventive Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Kiyomi Sakata
- Department of Hygiene and Preventive Medicine, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Akira Ogawa
- Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Seiichiro Kobayashi
- Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun, Iwate, 028-3694, Japan
| | - Koji Suzuki
- Department of Preventive Medical Sciences, Fujita Health University School of Medical Sciences, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, 470-1192, Japan.
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He Y, Hwang S, Cai Y, Kim SJ, Xu M, Yang D, Guillot A, Feng D, Seo W, Hou X, Gao B. MicroRNA-223 Ameliorates Nonalcoholic Steatohepatitis and Cancer by Targeting Multiple Inflammatory and Oncogenic Genes in Hepatocytes. Hepatology 2019; 70:1150-1167. [PMID: 30964207 PMCID: PMC6783322 DOI: 10.1002/hep.30645] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 04/03/2019] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases ranging from simple steatosis to more severe forms of liver injury including nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). In humans, only 20%-40% of patients with fatty liver progress to NASH, and mice fed a high-fat diet (HFD) develop fatty liver but are resistant to NASH development. To understand how simple steatosis progresses to NASH, we examined hepatic expression of anti-inflammatory microRNA-223 (miR-223) and found that this miRNA was highly elevated in hepatocytes in HFD-fed mice and in human NASH samples. Genetic deletion of miR-223 induced a full spectrum of NAFLD in long-term HFD-fed mice including steatosis, inflammation, fibrosis, and HCC. Furthermore, microarray analyses revealed that, compared to wild-type mice, HFD-fed miR-223 knockout (miR-223KO) mice had greater hepatic expression of many inflammatory genes and cancer-related genes, including (C-X-C motif) chemokine 10 (Cxcl10) and transcriptional coactivator with PDZ-binding motif (Taz), two well-known factors that promote NASH development. In vitro experiments demonstrated that Cxcl10 and Taz are two downstream targets of miR-223 and that overexpression of miR-223 reduced their expression in cultured hepatocytes. Hepatic levels of miR-223, CXCL10, and TAZ mRNA were elevated in human NASH samples, which positively correlated with hepatic levels of several miR-223 targeted genes as well as several proinflammatory, cancer-related, and fibrogenic genes. Conclusion: HFD-fed miR-223KO mice develop a full spectrum of NAFLD, representing a clinically relevant mouse NAFLD model; miR-223 plays a key role in controlling steatosis-to-NASH progression by inhibiting hepatic Cxcl10 and Taz expression and may be a therapeutic target for the treatment of NASH.
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Affiliation(s)
- Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Yan Cai
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seung-Jin Kim
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Mingjiang Xu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Dingcheng Yang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Adrien Guillot
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Wonhyo Seo
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Xin Hou
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
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Gusscott S, Tamiro F, Giambra V, Weng AP. Insulin-like growth factor (IGF) signaling in T-cell acute lymphoblastic leukemia. Adv Biol Regul 2019; 74:100652. [PMID: 31543360 DOI: 10.1016/j.jbior.2019.100652] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 09/12/2019] [Accepted: 09/13/2019] [Indexed: 12/16/2022]
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer, characterized by an uncontrolled expansion and accumulation of T-cell progenitors. During leukemic progression, immature T cells grow abnormally and occupy the bone marrow compartment, thereby interfering with the production of normal blood cells. Pediatric T-ALL is curable with intensive chemotherapy, but there are significant, long-term side effects and ~20% of patients suffer relapse for which there are limited treatment options. Adult T-ALL in contrast is largely incurable and refractory/relapsed disease is common despite multi-agent chemotherapy (5-year overall survival of ~40%), and thus new therapeutic targets are needed. We have reported previously on the role of insulin-like growth factor (IGF) signaling in T-ALL, and shown that it exerts potent phenotypes in both leukemia stem cell and bulk tumor cell populations. Modulators of IGF signaling may thus prove useful in improving outcomes in patients with T-ALL. In this review, we summarize the most recent findings relating to IGF signaling in T-ALL and outline therapeutic options using clinically relevant IGF signaling modulators.
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Affiliation(s)
- Samuel Gusscott
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada
| | - Francesco Tamiro
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo, FG, Italy
| | - Vincenzo Giambra
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada; Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, 71013, San Giovanni Rotondo, FG, Italy
| | - Andrew P Weng
- Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
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Huerta-Zavala ML, Lopez-Castillejos ES, Requenez-Contreras JL, Granados-Riveron JT, Aquino-Jarquin G. A single miRNA and miRNA sponge expression system for efficient modulation of miR-223 availability in mammalian cells. J Gene Med 2019; 21:e3100. [PMID: 31166636 DOI: 10.1002/jgm.3100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 05/20/2019] [Accepted: 05/27/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Hundreds of microRNAs (miRNAs), comprising small non-coding RNAs of 20-24 nucleotides, have been discovered, although the entirety of their biological functions is poorly understood. Overexpression or suppression approaches are commonly performed to investigate the function of specific miRNAs. In the present study, we focused on generating a lentiviral vector-based strategy that enables hsa-miR-223-3p (miR-223) overexpression and suppression in the target cells for functional analysis of this miRNA easily and rapidly. METHODS The sequence that gives rise to miR-223 and the sequence generating the sponge RNA with four binding sites for miR-223 were cloned in pLVX-shRNA2 vector. The functionality of the vector to overexpress miR-223 was evaluated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assays, whereas the post-transcriptional regulation exerted by miR-223 was evaluated by luciferase reporter assays in AD-293 cells. The anti-miR-223 sponge activity with one binding site for miR-223 (pmCherry-anti-miR-223) was confirmed by qRT-PCR and the restoration of its target (IKKα) was evaluated by western blot assays in Jurkat cells. RESULTS The pLVX-miR-223 vector is functional for over-expressing miR-223 and regulates the mRNA of MDR1/ABCB1 at the post-transcriptional level in AD-293 cells. The anti-miR-223 sponge with one miR-223 binding site efficiently modulates the miR-223 availability and not the one with four sites. The over-expression of anti-miR-223 correlated with a decrease in the levels of miR-223 and, consequently, with an increase in the expression level of the IKKα protein in Jurkat cells. CONCLUSIONS This single miRNA and miRNA sponge expression system specifically alters the availability of miR-223 in mammalian cells.
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Affiliation(s)
- Mariel Lizbeth Huerta-Zavala
- Laboratorio de Investigación en Genómica, Genética y Bioinformática, Torre de Hemato-Oncología, Hospital Infantil de México, Cuauhtémoc, CDMX, Mexico
| | - Erika Sicahui Lopez-Castillejos
- Laboratorio de Investigación en Genómica, Genética y Bioinformática, Torre de Hemato-Oncología, Hospital Infantil de México, Cuauhtémoc, CDMX, Mexico
| | - José Luis Requenez-Contreras
- Laboratorio de Investigación en Genómica, Genética y Bioinformática, Torre de Hemato-Oncología, Hospital Infantil de México, Cuauhtémoc, CDMX, Mexico
| | - Javier Tadeo Granados-Riveron
- Laboratorio de Investigación en Genómica, Genética y Bioinformática, Torre de Hemato-Oncología, Hospital Infantil de México, Cuauhtémoc, CDMX, Mexico
| | - Guillermo Aquino-Jarquin
- Laboratorio de Investigación en Genómica, Genética y Bioinformática, Torre de Hemato-Oncología, Hospital Infantil de México, Cuauhtémoc, CDMX, Mexico
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Zhang Q, Lin L, Li W, Lu G, Li X. MiR-223 inhibitor suppresses proliferation and induces apoptosis of thyroid cancer cells by down-regulating aquaporin-1. J Recept Signal Transduct Res 2019; 39:146-153. [PMID: 31311397 DOI: 10.1080/10799893.2019.1638403] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
To investigate the effect of miR-223 on thyroid cancer cells, further to study its potential mechanisms. The difference in miR-223 expression between normal thyroid Nthy-ori3-l cells and thyroid cancer SW579 cells was detected by PCR. The miR-223 overexpression and silencing vector transfection were verified by qRT-PCR. To further investigate the role of miR-223 in AQP-1, the AQP-1 siRNA vector was transfected on the basis of transfection of miR-223 inhibitor vector. The cell proliferation was detected by plate cloning, MTT, and cellular immunofluorescence assays. Cell cycle and apoptosis were detected by flow cytometry. Western blot was used to detect the expression of AQP-1 protein. The expression of miR-223 in SW579 cells was higher than that in normal cells. After transfection with miR-223 mimic, miR-223 expression was increased in SW579 cells. MiR-223 inhibitor transfection can inhibit SW579 cells proliferation, promote apoptosis, and inhibit cell cycle G0/G1 arrest. The SW579 cells proliferation was decreased, and the apoptosis rate was increased after transfection of AQP-1 silencing vector. Compared with the AQP-1 siRNA group, the SW579 cells proliferation rate was further reduced, and the apoptosis rate was significantly increased after co-transfection of miR-223 silencing vector and AQP-1 silencing vector. AQP-1 protein was highly expressed in SW579 cells, and miR-223 inhibitor can down-regulate the expression of APQ-1 protein. The expression AQP-1 protein was significantly reduced after transfected with AQP-1 silencing vector. Inhibition of miR-223 expression could suppress proliferation and promote apoptosis of SW579, and its mechanism is related to down-regulation of APQ-1 protein expression.
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Affiliation(s)
- Qiang Zhang
- a Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Lejun Lin
- b Department of Nuclear Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Weilong Li
- b Department of Nuclear Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Guowei Lu
- a Department of Otorhinolaryngology Head and Neck Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
| | - Xinna Li
- c Department of Pathology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University , Yantai , China
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Study of serum microRNA19a and microRNA223 as potential biomarkers for early diagnosis of hepatitis C virus-related hepatocellular carcinoma. GENE REPORTS 2019. [DOI: 10.1016/j.genrep.2019.100398] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Biological Aspects of mTOR in Leukemia. Int J Mol Sci 2018; 19:ijms19082396. [PMID: 30110936 PMCID: PMC6121663 DOI: 10.3390/ijms19082396] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Revised: 08/07/2018] [Accepted: 08/10/2018] [Indexed: 02/07/2023] Open
Abstract
The mammalian target of rapamycin (mTOR) is a central processor of intra- and extracellular signals, regulating many fundamental cellular processes such as metabolism, growth, proliferation, and survival. Strong evidences have indicated that mTOR dysregulation is deeply implicated in leukemogenesis. This has led to growing interest in the development of modulators of its activity for leukemia treatment. This review intends to provide an outline of the principal biological and molecular functions of mTOR. We summarize the current understanding of how mTOR interacts with microRNAs, with components of cell metabolism, and with controllers of apoptotic machinery. Lastly, from a clinical/translational perspective, we recapitulate the therapeutic results in leukemia, obtained by using mTOR inhibitors as single agents and in combination with other compounds.
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MiR-99b-5p and miR-203a-3p Function as Tumor Suppressors by Targeting IGF-1R in Gastric Cancer. Sci Rep 2018; 8:10119. [PMID: 29973668 PMCID: PMC6031697 DOI: 10.1038/s41598-018-27583-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 04/05/2018] [Indexed: 01/19/2023] Open
Abstract
MicroRNAs (miRNAs) have been explored in many critical cellular processes, including proliferation and apoptosis. The purpose of this study was to detect the biological function and regulation of miR-99b-5p and miR-203a-3p in gastric cancer (GC). Here, we demonstrated that miR-99b-5p/203a-3p were downregulated in both GC tissues and cell lines. MiR-99b-5p/203a-3p overexpression reduced GC cell proliferation and cell cycle progression in vitro. Notably, we combined bioinformatics tools with biological validation assays to demonstrate that insulin-like growth factor 1 receptor (IGF-1R) is a direct co-target and functional mediator of miR-99b-5p/203a-3p in GC cells. Mechanistically, the AKT pathway, which is downstream of IGF-1R, is essential for the functional roles of miR-99b-5p/203a-3p in GC cells. Taken together, our data revealed that IGF-1R is a direct co-target of miR-99b-5p/203a-3p, and miR-99b-5p/203a-3p may function as tumor suppressive miRNAs by negatively regulating IGF-1R expression in GC cells.
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Ding Q, Shen L, Nie X, Lu B, Pan X, Su Z, Yan A, Yan R, Zhou Y, Li L, Xu J. MiR-223-3p overexpression inhibits cell proliferation and migration by regulating inflammation-associated cytokines in glioblastomas. Pathol Res Pract 2018; 214:1330-1339. [PMID: 30033329 DOI: 10.1016/j.prp.2018.05.012] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 05/01/2018] [Accepted: 05/15/2018] [Indexed: 02/08/2023]
Abstract
Glioblastoma(GBM) is most common brain tumor in adults. Currently standard treatments have limited effect to increase the survival, because there are still largely unclear mechanisms in glioblastoma development. miR-223 was involved in various types of cancer, however, the function of miR-223-3p in GBM was still unclear. In our study, real-time PCR was performed to exam the expression level of miR-223-3p and NLRP3 (Nucleotide-binding oligomerization domain(NOD)-like receptor family PYRIN domain containing-3) in GBM tissues. Following that, mimic or inhibitor of miR-223-3p were used to modulate miR-223-3p expression in GBM cell lines respectively. Then, we analyzed cell proliferation and migration by cell counting kit and transwell assay. Further, western blot was performed to detect several inflammation-associated cytokines level in GBM cell lines. We found that miR-223-3p was decreased but NLRP3 was increased in GBM tissues. Treatment with miR-223-3p mimic inhibits cell proliferation and migration via decreasing several inflammation-associated cytokines, including interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), IL-8 and IL-18. Importantly, these effects induced by miR-223-3p could be attenuated by NLRP3 overexpression, which was considered as one of target genes of miR-223-3p. In conclusion, these results indicated that miR-223-3p might act as a suppressor and a potential therapy target of GBM.
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Affiliation(s)
- Qiuping Ding
- Department of Surgery, Huzhou Central Hospital, Hongqi Road 198, Huzhou, 313000, Zhejiang, China
| | - Liang Shen
- Department of Neurosurgery, Huzhou Central Hospital, Hongqi Road 198, Huzhou, 313000, Zhejiang, China
| | - Xiaohu Nie
- Department of Neurosurgery, Huzhou Central Hospital, Hongqi Road 198, Huzhou, 313000, Zhejiang, China
| | - Bin Lu
- Department of Neurosurgery, Huzhou Central Hospital, Hongqi Road 198, Huzhou, 313000, Zhejiang, China
| | - Xuyan Pan
- Department of Neurosurgery, Huzhou Central Hospital, Hongqi Road 198, Huzhou, 313000, Zhejiang, China
| | - Zhongzhou Su
- Department of Neurosurgery, Huzhou Central Hospital, Hongqi Road 198, Huzhou, 313000, Zhejiang, China
| | - Ai Yan
- Department of Neurosurgery, Huzhou Central Hospital, Hongqi Road 198, Huzhou, 313000, Zhejiang, China
| | - Renfu Yan
- Department of Neurosurgery, Huzhou Central Hospital, Hongqi Road 198, Huzhou, 313000, Zhejiang, China
| | - Yue Zhou
- Department of Neurosurgery, Huzhou Central Hospital, Hongqi Road 198, Huzhou, 313000, Zhejiang, China
| | - Liqin Li
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Huzhou, Zhejiang, China
| | - Jie Xu
- Department of Neurosurgery, Huzhou Central Hospital, Hongqi Road 198, Huzhou, 313000, Zhejiang, China.
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Liu X, Deng Y, Xu Y, Jin W, Li H. MicroRNA-223 protects neonatal rat cardiomyocytes and H9c2 cells from hypoxia-induced apoptosis and excessive autophagy via the Akt/mTOR pathway by targeting PARP-1. J Mol Cell Cardiol 2018; 118:133-146. [PMID: 29608885 DOI: 10.1016/j.yjmcc.2018.03.018] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 03/17/2018] [Accepted: 03/27/2018] [Indexed: 01/15/2023]
Abstract
Myocardial infarction (MI), characterized by interruption of blood and oxygen to myocardium, is a common yet fatal cardiovascular event that causes progressive damage to myocardial tissue and eventually leads to heart failure. Previous studies have shown increased expression of microRNA-223 (miR-223) in infarcted myocardial tissues of humans and in rat models of MI. However, the role of miR-223 in cell survival during MI has not been elucidated. Thus, we aimed to investigate whether miR-223 participates in the regulation of cardiac ischemia-induced injury and to elucidate the underlying mechanisms of this process. qRT-PCR revealed that miR-223 expression levels are significantly upregulated in the myocardial tissues of rats with post-MI heart failure and in hypoxia-treated neonatal rat cardiomyocytes (NRCMs) and H9c2 cells, which indicates that miR-223 may be associated with chronic ischemia. We also transfected NRCMs and H9c2 cells with miR-223 mimics or inhibitors in vitro, and the results revealed that increasing miR-223 expression protected cells from hypoxia-induced apoptosis and excessive autophagy, whereas decreasing miR-223 expression had contrasting effects. Further exploration of the mechanism showed that poly(ADP-ribose) polymerase 1 (PARP-1) is a target gene of miR-223 and that silencing PARP-1 prevented hypoxia-induced cell injury; additionally, silencing PARP-1 blocked the aggravated impact of miR-223 inhibitors. Thus, PARP-1 mediates the protective effects of miR-223 in hypoxia-treated cardiomyocytes. We also investigated the involvement of the Akt/mTOR pathway in the above phenomena. We found that miR-223 overexpression and PARP-1 silencing positively regulated the Akt/mTOR pathway and that treating cells with NVP-BEZ235 (BEZ235), a novel dual Akt/mTOR inhibitor, could reverse the inhibitory effects of both the miR-223 mimics and PARP-1 siRNA on hypoxia-induced apoptosis and autophagy. Taken together, our findings showed that miR-223 protects NRCMs and H9c2 cells from hypoxia-induced apoptosis and excessive autophagy via the Akt/mTOR pathway by targeting PARP-1; thus, miR-223 may be a potential target in the treatment of MI in the future.
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Affiliation(s)
- Xiaoxiao Liu
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yunfei Deng
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yifeng Xu
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wei Jin
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Hongli Li
- Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Gou W, Zhang Z, Yang C, Li Y. MiR-223/Pknox1 axis protects mice from CVB3-induced viral myocarditis by modulating macrophage polarization. Exp Cell Res 2018. [PMID: 29524390 DOI: 10.1016/j.yexcr.2018.03.004] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Macrophage polarization plays a crucial role in regulating myocardial inflammation and injuries of coxsackievirus B3 (CVB3)-induced viral myocarditis (VM). It has been reported that miR-223 is a potent regulator of inflammatory responses that involved in macrophage polarization. However, the functional roles of miR-223 in CVB3-induced VM still remain unknown. Here, we found that miR-223 expression was significantly down-regulated in heart tissues and heart-infiltrating macrophages of CVB3-infected mice. Up-regulation of miR-223 in vivo protected the mice against CVB3-induced myocardial injuries characterized by the increased body weight and survival, enhanced left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), relieved inflammation, depressed creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and aspartate transaminase (AST) levels, reduced production of interferon (IFN)-γ, interleukin (IL)- 6 as well as increased IL-10. We subsequently found that miR-233 up-regulation significantly suppressed the expression of M1 markers (iNOS, TNF-α and CD 86), and promoted the expression of M2 markers (Arginase-1, Fizz-1 and CD 206) in vivo and in vitro. Furthermore, we confirmed that miR-223 directly targeted Pknox1 to inhibit its expression, and the expression of Pknox1 was inversely correlated with miR-223 expression in heart tissues and heart-infiltrating macrophages of CVB3-infected mice. Gain-of-function analyses indicated that Pknox1 overexpression partially reversed the polarization phenotypes regulated by miR-223 overexpression. Taken together, the data suggest that miR-223 protects against CVB3-induced inflammation and myocardial damage, which may partly attribute to the regulation of macrophage polarization via targeting Pknox1.
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Affiliation(s)
- Weihui Gou
- PICU, First Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun, Jilin 130021, China
| | - Zhen Zhang
- PICU, First Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun, Jilin 130021, China
| | - Chunfeng Yang
- PICU, First Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun, Jilin 130021, China
| | - Yumei Li
- PICU, First Hospital of Jilin University, 71 Xinmin Street, Chaoyang District, Changchun, Jilin 130021, China.
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Zhang C, Zhang J. Decreased expression of microRNA-223 promotes cell proliferation in hepatocellular carcinoma cells via the insulin-like growth factor-1 signaling pathway. Exp Ther Med 2018; 15:4325-4331. [PMID: 29725374 PMCID: PMC5920509 DOI: 10.3892/etm.2018.5929] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 12/08/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most harmful types of cancer. Previous studies have demonstrated that microRNA (miR)-223 is downregulated in the serum and tumor tissue of patients with HCC. The present study aimed to investigate the regulatory role of miR-223 on insulin-like growth factor-1 receptor (IGF-1R) and downstream factors in HCC. The Hep3B cell line was transfected with miR-223 mimic and inhibitor. Following transfection, cell proliferation was analyzed using a cell counting kit 8 assay and cellular apoptosis was assessed using flow cytometry. The expression of key molecules in the IGF-1 signaling pathway, including IGF-1R, protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) were determined using reverse transcription-quantitative polymerase chain reaction and western blot analysis. The results demonstrated that the mRNA and protein levels of IGF-1R were decreased in cells transfected with miR-223. Transfection with miR-223 also decreased cell proliferation and promoted cell apoptosis. Expression of total Akt and ERK, and their active forms phosphorylated Akt and ERK, were also downregulated following transfection with miR-223. By contrast, transfection with miR-223 inhibitor did not induce any effects on Hep3B cell proliferation and apoptosis, and did not affect the expression of key molecules in the IGF-1 pathway. Therefore, the results of the present study indicate that miR-223 decreases the proliferation and promotes the apoptosis of HCC cells. Its molecular mechanism of action may at least partially occur via the direct regulation of IGF-1R and indirect reduction of the downstream molecules Akt and ERK.
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Affiliation(s)
- Cheng Zhang
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China
| | - Jiamin Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Jinhua People's Hospital, Jinhua, Zhejiang 321000, P.R. China
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Ultimo S, Martelli AM, Zauli G, Vitale M, Calin GA, Neri LM. Roles and clinical implications of microRNAs in acute lymphoblastic leukemia. J Cell Physiol 2018; 233:5642-5654. [DOI: 10.1002/jcp.26290] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 11/14/2017] [Indexed: 12/17/2022]
Affiliation(s)
- Simona Ultimo
- Department of Morphology, Surgery and Experimental MedicineUniversity of FerraraFerraraItaly
| | - Alberto M. Martelli
- Department of Biomedical and Neuromotor SciencesUniversity of BolognaBolognaItaly
| | - Giorgio Zauli
- Department of Morphology, Surgery and Experimental MedicineUniversity of FerraraFerraraItaly
| | - Marco Vitale
- Department of Medicine and Surgery, Sport and Exercise Medicine Centre (SEM)University of ParmaParmaItaly
- CoreLabHospital‐University of ParmaParmaItaly
| | - George A. Calin
- Departments of Experimental Therapeutics and LeukemiaThe University of Texas MD Anderson Cancer CenterHoustonTexas
- Center for RNA Interference and Non‐Coding RNAsThe University of Texas MD Anderson Cancer CenterHoustonTexas
| | - Luca M. Neri
- Department of Morphology, Surgery and Experimental MedicineUniversity of FerraraFerraraItaly
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de Melo Maia B, Rodrigues IS, Akagi EM, Soares do Amaral N, Ling H, Monroig P, Soares FA, Calin GA, Rocha RM. MiR-223-5p works as an oncomiR in vulvar carcinoma by TP63 suppression. Oncotarget 2018; 7:49217-49231. [PMID: 27359057 PMCID: PMC5226502 DOI: 10.18632/oncotarget.10247] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 05/08/2016] [Indexed: 01/21/2023] Open
Abstract
MiR-223-5p has been previously mentioned to be associated with tumor metastasis in HPV negative vulvar carcinomas, such as in several other tumor types. In the present study, we hypothesized that this microRNA would be important in vulvar cancer carcinogenesis and progression. To investigate this, we artificially mimicked miR-223-5p expression in a cell line derived from lymph node metastasis of vulvar carcinoma (SW962) and performed in vitro assays. As results, lower cell proliferation (p < 0.01) and migration (p < 0.001) were observed when miR-223-5p was overexpressed. In contrast, increased invasive potential of these cells was verified (p < 0.004). In silico search indicated that miR-223-5p targets TP63, member of the TP53 family of proteins, largely described with importance in vulvar cancer. We experimentally demonstrated that this microRNA is capable to decrease levels of p63 at both mRNA and protein levels (p < 0.001, and p < 0.0001; respectively). Also, a significant inverse correlation was observed between miR-223-5p and p63 expressions in tumors from patients (p = 0.0365). Furthermore, low p63 protein expression was correlated with deeper tumor invasion (p = 0.0491) and lower patient overall survival (p = 0.0494). Our study points out miR-223-5p overexpression as a putative pathological mechanism of tumor invasion and a promising therapeutic target and highlights the importance of both miR-223-5p and p63 as prognostic factors in vulvar cancer. Also, it is plausible that the evaluation of p63 expression in vulvar cancer at the biopsy level may bring important contribution on prognostic establishment and in elaborating better surgical approaches for vulvar cancer patients.
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Affiliation(s)
- Beatriz de Melo Maia
- Molecular Morphology Laboratory, Anatomic Pathology Department, AC Camargo Cancer Center, São Paulo, Brazil.,Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Iara Santana Rodrigues
- Molecular Morphology Laboratory, Anatomic Pathology Department, AC Camargo Cancer Center, São Paulo, Brazil
| | - Erica Mie Akagi
- Molecular Morphology Laboratory, Anatomic Pathology Department, AC Camargo Cancer Center, São Paulo, Brazil
| | - Nayra Soares do Amaral
- Molecular Morphology Laboratory, Anatomic Pathology Department, AC Camargo Cancer Center, São Paulo, Brazil
| | - Hui Ling
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Paloma Monroig
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Fernando Augusto Soares
- Molecular Morphology Laboratory, Anatomic Pathology Department, AC Camargo Cancer Center, São Paulo, Brazil
| | - George Adrian Calin
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.,The Center for RNA Interference and Non-Coding RNAs, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Rafael Malagoli Rocha
- Gynecology Laboratory, Gynecologic Department Federal University of São Paulo, São Paulo, Brazil
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Cao M, Zheng L, Liu J, Dobleman T, Hu S, Go VLW, Gao G, Xiao GG. MicroRNAs as effective surrogate biomarkers for early diagnosis of oral cancer. Clin Oral Investig 2018; 22:571-581. [PMID: 29299731 DOI: 10.1007/s00784-017-2317-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 12/12/2017] [Indexed: 12/20/2022]
Abstract
BACKGROUND Oral squamous cell carcinomas (OC) are life-threatening diseases emerging as major international health concerns. OBJECTIVE Development of an efficient clinical strategy for early diagnosis of the disease is a key for reducing the death rate. Biomarkers are proven to be an effective approach for clinical diagnosis of cancer. Although mechanisms underlying regulation of oral malignancy are still unclear, microRNAs (miRNAs) as a group of small non-coded RNAs may be developed as the effective biomarkers used for early detection of oral cancer. METHODS A literature search was conducted using the databases of PubMed, Web of Science, and the Cochrane Library. The following search terms were used: miRNAs and oral cancer or oral carcinoma. A critical appraisal of the included studies was performed with upregulated miRNAs and downregulated miRNAs in oral cancer. RESULTS In this review, we summarize the research progress made in miRNAs for diagnosis of oral cancer. The involvement of miRNAs identified in signal transduction pathways in OC, including Ras/MAPK signaling, PI3K/AKT signaling, JAK/STAT signaling, Wnt/β-catenin signaling, Notch signaling, and TGF-β/SMAD signaling pathway. CONCLUSIONS A number of studies demonstrated that miRNAs may be developed as an ideal set of biomarkers used for early diagnosis and prognosis of cancers because of the stability in human peripheral blood and body fluids and availability of non-invasive approaches being developed for clinical utility. CLINICAL RELEVANCE These findings suggest that miRNAs as biomarkers may be useful for diagnosis of OC.
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Affiliation(s)
- Min Cao
- School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, 116024, China
| | - Lijuan Zheng
- Geriatric Department of Stomatology, Dalian Stomatology Hospital, Dalian, 116021, China
| | - Jianzhou Liu
- School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, 116024, China
| | - Thomas Dobleman
- Genomics and Functional Proteomics Laboratories, Creighton University Medical Center, Omaha, NE, 68131, USA
| | - Shen Hu
- School of Dentistry, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Vay Liang W Go
- UCLA Agi Hirshberg Center for Pancreatic Diseases, David Geffen School of Medicine at University of California Los Angeles, 900 Veteran Avenue, Warren Hall 13-146, Los Angeles, CA, 90095-1786, USA
| | - Ge Gao
- Faculty of Laboratory Medicine, Xiangya Medical College of Central South University, Changsha, 410013, China
| | - Gary Guishan Xiao
- School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian, 116024, China. .,Genomics and Functional Proteomics Laboratories, Creighton University Medical Center, Omaha, NE, 68131, USA. .,UCLA Agi Hirshberg Center for Pancreatic Diseases, David Geffen School of Medicine at University of California Los Angeles, 900 Veteran Avenue, Warren Hall 13-146, Los Angeles, CA, 90095-1786, USA.
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Li B, Lin Z, Liang Q, Hu Y, Xu WF. PAQR6 Expression Enhancement Suggests a Worse Prognosis in Prostate Cancer Patients. Open Life Sci 2018; 13:511-517. [PMID: 33817121 PMCID: PMC7874734 DOI: 10.1515/biol-2018-0061] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 11/01/2018] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE This study aimed to evaluate the expression of progestin and adipoQ receptor family member VI (PAQR6, mPRδ) in prostate cancer and to explore its role in prostate cancer progression. METHODS PAQR6 mRNA expression was evaluated based on the data obtained from the TCGA database and the GEO database. The prognostic value of PAQR6 was explored by Kaplan-Meier analysis. To investigate the role of PAQR6, it was depleted by siRNA in DU145 cells. The effects of depleting PAQR6 on DU145 cell viability and migration were determined by CCK8 assay, colony formation assay, and wound healing assay, respectively. The activation of MEK and ERK were analyzed by western blot. RESULTS PAQR6 mRNA expression was significantly up-regulated in prostate cancer tissues and correlated with lower survival rates (p=0.014). Furthermore, qPCR revealed that PAQR6 expression was elevated in DU145 and LNCaP cells compared with RWPE-2 cells. Depleting PAQR6 obviously suppressed DU145 cell proliferation and migration (p<0.01). In addition, the ratio of p-MEK/MEK and p-ERK/ERK was significantly reduced after silencing PAQR6 (p<0.01). CONCLUSION PAQR6 might play a facilitating role in prostate cancer development by regulating the MAPK signaling pathway. Moreover, it might serve as a potential predictor and therapeutic target in prostate cancer.
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Affiliation(s)
- Bin Li
- Department of Urology Surgery, The First People’s Hospital of Foshan, No.81 LingNan Road, Foshan, GuangDong 528000, P.R. China
| | - Zhe Lin
- Department of Urology Surgery, The First People’s Hospital of Foshan, No.81 LingNan Road, Foshan, GuangDong 528000, P.R. China
| | - Quan Liang
- Department of Urology Surgery, The First People’s Hospital of Foshan, No.81 LingNan Road, Foshan, GuangDong 528000, P.R. China
| | - Yuan Hu
- Department of Urology Surgery, The First People’s Hospital of Foshan, No.81 LingNan Road, Foshan, GuangDong 528000, P.R. China
| | - Wen-Feng Xu
- Department of Urology Surgery, The First People’s Hospital of Foshan, No.81 LingNan Road, Foshan, GuangDong 528000, P.R. China
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Wang R, Qi B, Dong YW, Cai QQ, Deng NH, Chen Q, Li C, Jin YT, Wu XZ. Sulfatide interacts with and activates integrin αVβ3 in human hepatocellular carcinoma cells. Oncotarget 2017; 7:36563-36576. [PMID: 27145276 PMCID: PMC5095021 DOI: 10.18632/oncotarget.9095] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 04/16/2016] [Indexed: 12/12/2022] Open
Abstract
Integrin αVβ3 is a malignant driver of anchorage-independence and tumor angiogenesis, but its dysregulation in hepatocellular carcinoma (HCC) remains unclear. In this study, we observed that sulfatide significantly promoted integrin αV(ITGAV) expression and wound closure in HCC. We also noted that elevated sulfatide profoundly stimulated integrin αVβ3 clustering and signaling. In the cells with integrin αVβ3 clustering induced by sulfatide, integrin β3 subunit was phosphorylated. Simultaneously, focal adhesion kinase (FAK), Src and paxillin were also phosphorylated. Treatment with FAK inhibitor resulted in robust suppression of FAK-Y397 and Src-Y416 phosphorylation stimulated by sulfatide, but not suppression of integrin β3 phosphorylation. Src inhibitors repressed Src-Y416 and FAK Y861 and Y925 phosphorylation, but not FAK-Y397 and integrin β3 phosphorylation. After mutation of integrin β3 (Y773F and Y785F), FAK or Src phosphorylation failed to be stimulated by sulfatide. Moreover, β3 Y773 and Y785 phosphorylation was suppressed by insulin-like growth factor receptor knockdown even in cells stimulated by sulfatide. In assays of immunoprecipitation and immunostaining with integrin αV or β3 antibody, labeled sulfatide was found in the complex and co-localized with integrin αVβ3. Taken together, this study demonstrated that elevated sulfatide bound to integrin αVβ3 and induced clustering and phosphorylation of αVβ3 instead of matrix ligand binding, triggering outside-in signaling.
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Affiliation(s)
- Rong Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR. China.,Key Laboratory of Glycoconjugate Research, Ministry of Public Health, Shanghai, PR. China
| | - Bing Qi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR. China.,Key Laboratory of Glycoconjugate Research, Ministry of Public Health, Shanghai, PR. China
| | - Yi Wei Dong
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR. China.,Key Laboratory of Glycoconjugate Research, Ministry of Public Health, Shanghai, PR. China
| | - Qian Qian Cai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR. China.,Key Laboratory of Glycoconjugate Research, Ministry of Public Health, Shanghai, PR. China
| | - Nian Hui Deng
- Yu Ying Children's Hospital, Wenzhou Medical University, Wenzhou, PR. China
| | - Qi Chen
- Yu Ying Children's Hospital, Wenzhou Medical University, Wenzhou, PR. China
| | - Chao Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR. China
| | - Yu Tong Jin
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR. China
| | - Xing Zhong Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, PR. China.,Key Laboratory of Glycoconjugate Research, Ministry of Public Health, Shanghai, PR. China
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Wan L, Yuan X, Liu M, Xue B. miRNA-223-3p regulates NLRP3 to promote apoptosis and inhibit proliferation of hep3B cells. Exp Ther Med 2017; 15:2429-2435. [PMID: 29467847 PMCID: PMC5792760 DOI: 10.3892/etm.2017.5667] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 08/18/2017] [Indexed: 01/20/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major malignant tumor type with a high incidence and mortality. Infection with hepatitis virus is a high-risk factor. Previous studies have demonstrated that microRNA (miR)-223 was downregulated in HCC tissues. NOD-like receptor family, pyrin domain containing 3 (NLRP3)-is a potential target of miR-223 and has a vital role in hepatitis infection. The present study was performed to investigate the role of miR-223 in the proliferation and apoptosis of HCC cells through regulating NLRP3. A dual luciferase reporter assay was performed to confirm the direct interaction between miR-223-3p and the 3′ untranslated region of NLRP3 mRNA. Hep3B cells were then transfected with miR-223 mimics and the proliferation and apoptosis were determined by an MTT and a flow cytometric assay, respectively. The expression of NLRP3 and caspase-1 was analyzed at the mRNA as well as at the protein level by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The secretion of interleukin (IL)-1β and IL-18 in the culture supernatants was measured by ELISA. The dual luciferase assay confirmed NLRP3 as a direct target of miR-223. Overexpression of miR-223 in hep3B cells significantly suppressed cell proliferation and promoted apoptosis. Furthermore, the expression of NLRP3 was downregulated by miR-223 transfection. Certain downstream factors of the NLRP3 pathway were also downregulated following overexpression of miR-223. Caspase-1 was decreased at the transcriptional level and the cleaved caspase-1 was decreased at the protein level. Secretion of IL-1β and IL-18 into the culture medium by cells transfected with miR-223 was lower than that by the control cells. In conclusion, the tumor suppressor role of miR-223 was associated with the regulation of NLRP3 inflammasome components. miR-223 inhibited HCC cell proliferation and promoted apoptosis by directly targeting NLRP3. Downstream production of caspase-1, IL-1β and IL-18 were also repressed by miR-223. These results provided insight into the association between the innate immune system and the genesis of HCC.
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Affiliation(s)
- Lingfeng Wan
- Department of Infectious Disease, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Xin Yuan
- Department of Internal Medicine, The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Mantian Liu
- Department of Infectious Disease, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Boyu Xue
- Department of Infectious Disease, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
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Kume K, Iwama H, Deguchi K, Ikeda K, Takata T, Kokudo Y, Kamada M, Fujikawa K, Hirose K, Masugata H, Touge T, Masaki T. Serum microRNA expression profiling in patients with multiple system atrophy. Mol Med Rep 2017; 17:852-860. [PMID: 29115515 PMCID: PMC5780164 DOI: 10.3892/mmr.2017.7995] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Accepted: 04/26/2017] [Indexed: 12/12/2022] Open
Abstract
Multiple system atrophy (MSA) is a sporadic neurodegenerative disease that is pathologically characterized by α-synuclein positive glial cytoplasmic inclusions in oligodendrocytes. The clinical diagnosis of MSA is often challenging as there are no established biomarkers and diagnoses are now based on clinical findings alone. At present, the etiology and pathogenesis of MSA are unclear. It has been reported that dysregulation of microRNA (miRNA/miR) serves an important role in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The miRNA profile of patients with MSA remains to be established. The present study investigated the serum miRNA expression level of 10 patients with MSA, using microarray chips including 668 miRNAs. It was identified that 50 miRNAs were significantly upregulated and 17 miRNAs were significantly downregulated in the serum of the patients with MSA. The most upregulated miRNA was miR-16, which may induce the accumulation of α-synuclein. The target genes of some miRNAs upregulated in MSA (including miR-17, 20a, 24, 25, 30d and 451) were associated with autophagy-associated molecules. The present study concluded that the expression pattern of miRNAs may be a clinical biomarker for MSA and targeting these miRNAs may provide a novel treatment for MSA.
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Affiliation(s)
- Kodai Kume
- Department of Neurology, Kagawa University Hospital, Kita‑gun, Kagawa 761‑0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Faculty of Medicine, Kagawa University, Kita‑gun, Kagawa 761‑0793, Japan
| | - Kazushi Deguchi
- Department of Neurology, Kagawa University Hospital, Kita‑gun, Kagawa 761‑0793, Japan
| | - Kazuyo Ikeda
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita‑gun, Kagawa 761‑0793, Japan
| | - Tadayuki Takata
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita‑gun, Kagawa 761‑0793, Japan
| | - Yohei Kokudo
- Department of Intractable Neurological Research, Faculty of Medicine, Kagawa University, Kita‑gun, Kagawa 761‑0793, Japan
| | - Masaki Kamada
- Department of Intractable Neurological Research, Faculty of Medicine, Kagawa University, Kita‑gun, Kagawa 761‑0793, Japan
| | - Keiko Fujikawa
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita‑gun, Kagawa 761‑0793, Japan
| | - Kayo Hirose
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita‑gun, Kagawa 761‑0793, Japan
| | - Hisashi Masugata
- Department of Integrated Medicine, Faculty of Medicine, Kagawa University, Kita‑gun, Kagawa 761‑0793, Japan
| | - Tetsuo Touge
- Department of Health Sciences, Faculty of Medicine, Kagawa University, Kita‑gun, Kagawa 761‑0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita‑gun, Kagawa 761‑0793, Japan
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Liu L, Zhang C, Li X, Sun W, Qin S, Qin L, Wang X. miR-223 promotes colon cancer by directly targeting p120 catenin. Oncotarget 2017; 8:63764-63779. [PMID: 28969027 PMCID: PMC5609959 DOI: 10.18632/oncotarget.19541] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 06/19/2017] [Indexed: 12/24/2022] Open
Abstract
microRNA (miRNA) dysregulation is frequently observed in colon cancer. Previous studies found that miR-223 is upregulated in colon cancer and functions as an oncogene. Conversely, p120 is often downregulated or even absent in colon cancer, and is a likely tumor suppressor. The present study showed that increased miR-223 and decreased p120 levels are associated with colon cancer malignancy, and p120 expression is negatively correlated with miR-223 expression. A dual luciferase reporter assay showed that miR-223 directly targets p120. miR-223 upregulation in a colon cancer cell line upregulated c-Myc, cyclinD1, MMP7, and vimentin expression, downregulated E-cadherin, increased nuclear expression of β-catenin, and enhanced RhoA activation. We suggest miR-223 may promote colon cancer cell invasion and metastasis by downregulating p120, thereby reducing intercellular adhesion, promoting RhoA activity, and activating β-catenin signaling. Thus miR-223 functions as an oncogene in colon cancer and may be a potential diagnostic and therapeutic target for anti-colon cancer treatment.
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Affiliation(s)
- Liwei Liu
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chao Zhang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiyu Li
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Wenjia Sun
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shenghui Qin
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lingzhi Qin
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xi Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Gao Y, Lin L, Li T, Yang J, Wei Y. The role of miRNA-223 in cancer: Function, diagnosis and therapy. Gene 2017; 616:1-7. [PMID: 28322994 DOI: 10.1016/j.gene.2017.03.021] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2016] [Revised: 01/28/2017] [Accepted: 03/16/2017] [Indexed: 01/01/2023]
Abstract
MicroRNAs (miRNAs) constitute a large family of small, non-coding RNAs with the capacity to regulate gene expression post-transcriptionally. miRNAs appear to hold promise of mechanistic explanations for various physiological and pathological processes. miRNA-223 is highly conserved and preferentially expressed in the hematopoietic system in regulation of myeloid differentiation. Recently, increasing evidence suggests that miRNA-223 may also play an essential part in both hematological malignancies and solid tumors. miRNA-223 can function as either an oncogene or a tumor suppressor gene, which is achieved by targeting a wide range of genes and regulating downstream signal transduction. As yet, the function of miR-223 in cancer has not been fully characterized and understood. To make it more clear, this review firstly summarizes the present understanding of the regulation of miR-223 at the molecular level, its crucial role in oncogenesis, development, and metastasis, its function as a diagnostic and prognostic biomarker and finally, its potential applications in monitoring and therapy of diverse types of malignancies.
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Affiliation(s)
- Yunliang Gao
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China; Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, United States
| | - Le Lin
- Department of Urology, Fujian Medical University Teaching Hospital, Fujian Provincial Hospital, Fuzhou 350001, PR China
| | - Tao Li
- Department of Urology, Fujian Medical University Teaching Hospital, Fujian Provincial Hospital, Fuzhou 350001, PR China
| | - Jinrui Yang
- Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China.
| | - Yongbao Wei
- Department of Urology, Fujian Medical University Teaching Hospital, Fujian Provincial Hospital, Fuzhou 350001, PR China.
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miR-195 Regulates Proliferation and Apoptosis through Inhibiting the mTOR/p70s6k Signaling Pathway by Targeting HMGA2 in Esophageal Carcinoma Cells. DISEASE MARKERS 2017; 2017:8317913. [PMID: 28487599 PMCID: PMC5402242 DOI: 10.1155/2017/8317913] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 02/13/2017] [Accepted: 03/13/2017] [Indexed: 12/19/2022]
Abstract
miR-195 is related to tumorigenesis and frequently inhibits cell proliferation and promotes apoptosis in various cancers, including esophageal carcinoma (EC). The mTOR/p70s6k signaling pathway, which is the major target pathway for HMGA2, regulates the survival and cell proliferation of many tumors and is commonly active in EC. The relationships of miR-195, HMGA2, and the mTOR/p70s6k signaling pathway in EC, however, remain unknown. In the present study, we found that the miR-195 level was significantly downregulated in EC tissues, while the mRNA expressions of HMGA2 were significantly upregulated. Dual-luciferase reporter assay demonstrated that HMGA2 is a target of miR-195. MTT assay and flow cytometry revealed that miR-195 overexpression inhibited cell proliferation and induced apoptosis by targeting HMGA2. We also found that HMGA2 restored the inhibitory effect of miR-195 on phosphorylation of mTOR and p70S6K. Furthermore, rapamycin, a specific inhibitor of the mTOR/p70S6K signaling pathway, decreased the levels of Ki-67 and Bcl-2/Bax ratio, inhibited cell proliferation, and promoted apoptosis in EC cells. In conclusion, upregulation of miR-195 significantly suppressed cell growth and induced apoptosis of EC cells via suppressing the mTOR/p70s6k signaling pathway by targeting HMGA2.
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Xiao Q, Ye QF, Wang W, Fu BQ, Xia ZP, Liu ZZ, Zhang XJ, Wang YF. Mild hypothermia pretreatment protects hepatocytes against ischemia reperfusion injury via down-regulating miR-122 and IGF-1R/AKT pathway. Cryobiology 2017; 75:100-105. [DOI: 10.1016/j.cryobiol.2017.01.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 11/05/2016] [Accepted: 01/13/2017] [Indexed: 12/19/2022]
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Du X, Wang Z, Liu X, Liu X, Wang Y. Withdrawn: The effects of MiR-223 on the sensitivity of non-small cell lung cancer cells to erlotinib and its underlying mechanisms. Saudi Pharm J 2017. [DOI: 10.1016/j.jsps.2017.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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