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Mohamed Abdelgawwad El-Sehrawy AA, Mohammed MH, Salahldin OD, Uthirapathy S, Ballal S, Kalia R, Arya R, Joshi KK, Kadim AS, Kadhim AJ. Crosstalk between microRNA and inflammation; critical regulator of diabetes. Exp Cell Res 2025; 447:114507. [PMID: 40058448 DOI: 10.1016/j.yexcr.2025.114507] [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: 01/13/2025] [Revised: 03/06/2025] [Accepted: 03/06/2025] [Indexed: 03/25/2025]
Abstract
A growing body of evidence indicates that microRNAs (miRNAs may be used as biomarkers for the diagnosis, prognosis, and treatment of diabetes, given their changed expression profile as the disease progresses. There is growing interest in using individual miRNAs or whole miRNA clusters linked to diabetes as therapeutic targets because of their abnormal expression and functioning. In diabetes, miRNAs are also involved in inflammatory and immunological responses. Additionally, the inflammatory response controls the generation, processing, and stability of pre- or mature miRNAs and miRNA biogenesis. With a comprehensive grasp of molecular biological activities and the signaling axis, this review emphasizes the critical functions of miRNAs in inflammatory and immunological processes in diabetes. We further emphasized the potential role of these miRNAs in controlling inflammation associated with diabetes. This assessment will direct the shift from many studies to practical applications for tailored diabetes treatment and assist in identifying new therapeutic targets and approaches.
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Affiliation(s)
| | - Mohammed Hashim Mohammed
- Medical Laboratory Techniques Department, College of Health and Medical Technology, Al-maarif University, Anbar, Iraq.
| | | | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq.
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India.
| | - Rishiv Kalia
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India.
| | - Renu Arya
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, 140307, Punjab, India.
| | - Kamal Kant Joshi
- Department of Allied Science, Graphic Era Hill University, Dehradun, 248002, Uttarakhand, India; Graphic Era Deemed to Be University, Dehradun, Uttarakhand, India.
| | - Arshed Shakir Kadim
- Radiological Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, Babylon, 51001, Iraq.
| | - Abed J Kadhim
- Department of Medical Engineering, Al-Nisour University College, Baghdad, Iraq.
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Yuan L, Jiang X, Gong Q, Gao N. Arsenic resistance protein 2 and microRNA biogenesis: Biological implications in cancer development. Pharmacol Ther 2023; 244:108386. [PMID: 36933704 DOI: 10.1016/j.pharmthera.2023.108386] [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: 01/01/2023] [Revised: 03/12/2023] [Accepted: 03/15/2023] [Indexed: 03/18/2023]
Abstract
Arsenic resistance protein 2 (Ars2) is a nuclear protein that plays a critical role in the regulation of microRNA (miRNA) biogenesis. Ars2 is required for cell proliferation and for the early stages of mammalian development through a possible effect on miRNA processing. Increasing evidence reveal that Ars2 is highly expressed in proliferating cancer cells, suggesting that Ars2 may be a potential therapeutic target for cancer. Therefore, development of the novel Ars2 inhibitors could represent the novel therapeutic strategies for treatment of cancer. In this review, we briefly discuss the mechanisms by which Ars2 regulates miRNA biogenesis and its impact on cell proliferation and cancer development. Particularly, we mainly discuss the role of Ars2 in the regulation of cancer development and highlight pharmacological targeting of Ars2 as a promising cancer therapeutic strategy.
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Affiliation(s)
- Liang Yuan
- Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563006, China
| | - Xiuxing Jiang
- College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China
| | - Qihai Gong
- Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563006, China.
| | - Ning Gao
- Key Laboratory of Basic Pharmacology of Ministry of Education, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563006, China.
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Mamedova EO, Dimitrova DA, Belaya ZE, Melnichenko GA. [The role of non-coding RNAs in the pathogenesis of multiple endocrine neoplasia syndrome type 1]. ACTA ACUST UNITED AC 2020; 66:4-12. [PMID: 33351343 DOI: 10.14341/probl12413] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/02/2020] [Accepted: 06/15/2020] [Indexed: 01/03/2023]
Abstract
Changes in the expression of non-coding ribonucleic acids (ncRNAs) take part in the formation of various tumors. Multiple endocrine neoplasia syndrome type 1 (MEN1) is a rare autosomal dominant disease caused by mutations of the MEN1 gene encoding the menin protein. This syndrome is characterized by the occurrence of parathyroid tumors, gastroenteropancreatic neuroendocrine tumors, pituitary adenomas, as well as other endocrine and non-endocrine tumors. The pathogenesis of MEN-1 associated tumors due to MEN1 mutations remains unclear. In the absence of mutations of the MEN1 gene in patients with phenotypically similar features, this condition is regarded as a phenocopy of this syndrome. The cause of the combination of several MEN-1-related tumors in these patients remains unknown. The possible cause is that changes in the expression of ncRNAs affect the regulation of signaling pathways in which menin participates and may contribute to the development of MEN-1-related tumors. The identification of even a small number of agents interacting with menin makes a significant contribution to the improvement of knowledge about its pathophysiological influence and ways of developing tumors within the MEN-1 syndrome and its phenocopies.
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Zhu Z, Zhang Y, Bai R, Yang R, Shan Z, Ma C, Yang J, Sun D. Association of Genetic Polymorphisms in MicroRNAs With Type 2 Diabetes Mellitus in a Chinese Population. Front Endocrinol (Lausanne) 2020; 11:587561. [PMID: 33628196 PMCID: PMC7897684 DOI: 10.3389/fendo.2020.587561] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 12/21/2020] [Indexed: 01/04/2023] Open
Abstract
INTRODUCTION MicroRNAs (miRNA) involved in the insulin signaling pathways deeply affect the pathogenesis of T2DM. The aim of this study was to assess the association between single nucleotide polymorphisms (SNP) of the related miRNAs (let-7f rs10877887, let-7a-1 rs13293512, miR-133a-1 rs8089787, miR-133a-2 rs13040413, and miR-27a rs895819) and susceptibility to type 2 diabetes mellitus (T2DM), and its possible mechanisms. METHODS Five SNPs in miRNAs (let-7f rs10877887, let-7a-1 rs13293512, miR-133a-1 rs8089787, miR-133a-2 rs13040413, and miR-27a rs895819) involved in the insulin signaling pathways were selected and genotyped in a case-control study that enrolled 371 T2DM patients and 381 non-diabetic controls. The individual SNP association analyses, interaction analyses of SNP-SNP, SNP-environmental factors were performed. The effect the risk-associated polymorphism on regulating its mature miRNA expression was also evaluated. RESULTS In overall analyses, miR-133a-2 rs13040413 and let-7a-1 rs13293512 were related to the susceptibility to T2DM. In stratified analyses, miR-133a-2 rs13040413, let-7a-1 rs13293512 and miR-27a rs895819 showed associations with T2DM in the age ≥ 60 years subgroup. Moreover, let-7a-1 rs13293512 and miR-27a rs895819 showed associations with T2DM in male subgroup. In SNP-environmental factors interaction analyses, there were interaction effects of miR-133a-2 rs13040413 with dyslipidemia, let-7a-1 rs13293512 with smoking, and let-7a-1 rs13293512 with dyslipidemia on T2DM. In SNP-SNP interaction analyses, there were also interaction effects of miR-133a-1 rs8089787 with let-7a-1 rs13293512, and miR-133a-1 rs8089787 with let-7f rs10877887 on T2DM. Furthermore, for miR-133a-2 rs13040413, the variant T allele showed a trend toward decreased miR-133a expression in comparison with the wild C allele. For let-7a-1 rs13293512, the variant C allele expressed a lower let-7a compared to the wild T allele. CONCLUSION MiRNAs polymorphisms involved in the insulin signaling pathways and the interaction effects of SNP-SNP, SNP-environmental factors were related to T2DM susceptibility in a Chinese population.
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Affiliation(s)
- Zaihan Zhu
- Department of Cardiovascular Ultrasound, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yanfen Zhang
- Department of Cardiovascular Ultrasound, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ruocen Bai
- Department of Cardiovascular Ultrasound, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Ru Yang
- Department of Cardiovascular Ultrasound, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhongyan Shan
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Chunyan Ma
- Department of Cardiovascular Ultrasound, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jun Yang
- Department of Cardiovascular Ultrasound, The First Affiliated Hospital of China Medical University, Shenyang, China
- *Correspondence: Dandan Sun, ; Jun Yang,
| | - Dandan Sun
- Department of Cardiovascular Ultrasound, The First Affiliated Hospital of China Medical University, Shenyang, China
- *Correspondence: Dandan Sun, ; Jun Yang,
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Mziaut H, Henniger G, Ganss K, Hempel S, Wolk S, McChord J, Chowdhury K, Ravassard P, Knoch KP, Krautz C, Weitz J, Grützmann R, Pilarsky C, Solimena M, Kersting S. MiR-132 controls pancreatic beta cell proliferation and survival through Pten/Akt/Foxo3 signaling. Mol Metab 2019; 31:150-162. [PMID: 31918917 PMCID: PMC6928290 DOI: 10.1016/j.molmet.2019.11.012] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 11/09/2019] [Accepted: 11/15/2019] [Indexed: 12/16/2022] Open
Abstract
Objective MicroRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. Deciphering their targets and precise role, however, remains challenging. In this study, we aimed to identify miRNAs and their downstream targets involved in the regeneration of islet beta cells following partial pancreatectomy in mice. Methods RNA from laser capture microdissected (LCM) islets of partially pancreatectomized and sham-operated mice were profiled with microarrays to identify putative miRNAs implicated in beta cell regeneration. Altered expression of the selected miRNAs, including miR-132, was verified by RT-PCR. Potential targets of miR-132 were selected through bioinformatic data mining. Predicted miR-132 targets were validated for their changed RNA, protein expression levels, and signaling upon miR-132 knockdown and/or overexpression in mouse MIN6 and human EndoC-βH1 insulinoma cells. The ability of miR-132 to foster beta cell proliferation in vivo was further assessed in pancreatectomized miR-132−/− and control mice. Results Partial pancreatectomy significantly increased the number of BrdU+/insulin+ islet cells. Microarray profiling revealed that 14 miRNAs, including miR-132 and -141, were significantly upregulated in the LCM islets of the partially pancreatectomized mice compared to the LCM islets of the control mice. In the same comparison, miR-760 was the only downregulated miRNA. The changed expression of these miRNAs in the islets of the partially pancreatectomized mice was confirmed by RT-PCR only in the case of miR-132 and -141. Based on previous knowledge of its function, we focused our attention on miR-132. Downregulation of miR-132 reduced the proliferation of MIN6 cells while enhancing the levels of pro-apoptotic cleaved caspase-9. The opposite was observed in miR-132 overexpressing MIN6 cells. Microarray profiling, RT-PCR, and immunoblotting of the latter cells demonstrated their downregulated expression of Pten with concomitant increased levels of pro-proliferative factors phospho-Akt and phospho-Creb and inactivation of pro-apoptotic Foxo3a via its phosphorylation. Downregulation of Pten was further confirmed in the LCM islets of pancreatectomized mice compared to the sham-operated mice. Moreover, overexpression of miR-132 correlated with increased proliferation of EndoC-βH1 cells. The regeneration of beta cells following partial pancreatectomy was lower in the miR-132/212−/− mice than the control littermates. Conclusions This study provides compelling evidence about the critical role of miR-132 for the regeneration of mouse islet beta cells through the downregulation of its target Pten. Hence, the miR-132/Pten/Akt/Foxo3 signaling pathway may represent a suitable target to enhance beta cell mass.
miR-132 is induced in mouse islets upon partial pancreatectomy. miR-132 promotes regeneration of β-cells in vivo following partial pancreatectomy. miR-132 fosters in vitro proliferation/survival through Pten/Akt/Foxo3 signaling. Downstream targets of miR-132 were identified in pancreatic β-cells. miR-132−/− mice have impaired β-cell proliferation.
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Affiliation(s)
- Hassan Mziaut
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Georg Henniger
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Katharina Ganss
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Sebastian Hempel
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Steffen Wolk
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Johanna McChord
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Kamal Chowdhury
- Max Planck Institute of Biophysical Chemistry, Göttingen, Germany
| | - Philippe Ravassard
- Sorbonne Universités, UPMC Univ Paris 06, INSERM U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle Épinière, ICM, F-75013, Paris, France
| | - Klaus-Peter Knoch
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Christian Krautz
- Department of Surgery, University of Erlangen, Erlangen, Germany
| | - Jürgen Weitz
- Department of General, Thoracic, and Vascular Surgery, Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Robert Grützmann
- Department of Surgery, University of Erlangen, Erlangen, Germany
| | | | - Michele Solimena
- Molecular Diabetology, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany; Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital and Faculty of Medicine of TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
| | - Stephan Kersting
- Department of Surgery, University of Erlangen, Erlangen, Germany.
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Lines KE, Newey PJ, Yates CJ, Stevenson M, Dyar R, Walls GV, Bowl MR, Thakker RV. MiR-15a/miR-16-1 expression inversely correlates with cyclin D1 levels in Men1 pituitary NETs. J Endocrinol 2018; 240:JOE-18-0278.R2. [PMID: 30389902 PMCID: PMC6347280 DOI: 10.1530/joe-18-0278] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 09/28/2018] [Indexed: 12/19/2022]
Abstract
Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic islet tumours, and is due to mutations of the MEN1 gene, which encodes the tumour suppressor protein menin. Menin has multiple roles in genome stability, transcription, cell division and proliferation, but its mechanistic roles in tumourigenesis remain to be fully elucidated. MicroRNAs (miRNA) are non-coding single stranded RNAs that post-transcriptionally regulate gene expression and have been associated with tumour development, although the contribution of miRNAs to MEN1-associated tumourigenesis and their relationship with menin expression are not fully understood. Alterations in miRNA expression, including downregulation of three putative 'tumour suppressor' miRNAs, miR-15a, miR-16-1 and let-7a, have been reported in several tumour types including non-MEN1 pituitary adenomas. We have therefore investigated the expression of miR-15a, miR-16-1 and let-7a in pituitary tumours that developed after 12 months of age in female mice with heterozygous knock out of the Men1 gene (Men1+/- mice). The miRNAs miR-15a, miR-16-1 and let-7a were significantly downregulated in pituitary tumours (by 2.3-fold, p<0.05; 2.1-fold p<0.01 and 1.6-fold p<0.05, respectively) of Men1+/- mice, compared to normal wild type pituitaries. MiR-15a and miR-16-1 expression inversely correlated with expression of cyclin D1, a known pro-tumourigenic target of these miRNAs, and knock down of menin in a human cancer cell line (HeLa), and AtT20 mouse pituitary cell line resulted in significantly decreased expression of miR-15a (p<0.05), indicating that the decrease in miR-15a may be a direct result of lost menin expression.
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Affiliation(s)
- K E Lines
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK
| | - P J Newey
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK
- Division of Molecular & Clinical Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK
| | - C J Yates
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK
| | - M Stevenson
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK
| | - R Dyar
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK
| | - G V Walls
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK
| | - M R Bowl
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK
| | - R V Thakker
- Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Churchill Hospital, Headington, Oxford, UK
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Feng Z, Ma J, Hua X. Epigenetic regulation by the menin pathway. Endocr Relat Cancer 2017; 24:T147-T159. [PMID: 28811300 PMCID: PMC5612327 DOI: 10.1530/erc-17-0298] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 08/15/2017] [Indexed: 02/06/2023]
Abstract
There is a trend of increasing prevalence of neuroendocrine tumors (NETs), and the inherited multiple endocrine neoplasia type 1 (MEN1) syndrome serves as a genetic model to investigate how NETs develop and the underlying mechanisms. Menin, encoded by the MEN1 gene, at least partly acts as a scaffold protein by interacting with multiple partners to regulate cellular homeostasis of various endocrine organs. Menin has multiple functions including regulation of several important signaling pathways by controlling gene transcription. Here, we focus on reviewing the recent progress in elucidating the key biochemical role of menin in epigenetic regulation of gene transcription and cell signaling, as well as posttranslational regulation of menin itself. In particular, we will review the progress in studying structural and functional interactions of menin with various histone modifiers and transcription factors such as MLL, PRMT5, SUV39H1 and other transcription factors including c-Myb and JunD. Moreover, the role of menin in regulating cell signaling pathways such as TGF-beta, Wnt and Hedgehog, as well as miRNA biogenesis and processing will be described. Further, the regulation of the MEN1 gene transcription, posttranslational modifications and stability of menin protein will be reviewed. These various modes of regulation by menin as well as regulation of menin by various biological factors broaden the view regarding how menin controls various biological processes in neuroendocrine organ homeostasis.
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Affiliation(s)
- Zijie Feng
- Department of Cancer BiologyAbramson Family Cancer Research Institute, Abramson Cancer Center, Institute of Diabetes, Obesity, and Metabolism (IDOM), University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jian Ma
- Department of Cancer BiologyAbramson Family Cancer Research Institute, Abramson Cancer Center, Institute of Diabetes, Obesity, and Metabolism (IDOM), University of Pennsylvania, Philadelphia, Pennsylvania, USA
- State Key Laboratory of Veterinary BiotechnologyHarbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, Heilongjiang, China
| | - Xianxin Hua
- Department of Cancer BiologyAbramson Family Cancer Research Institute, Abramson Cancer Center, Institute of Diabetes, Obesity, and Metabolism (IDOM), University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Muhammad AB, Xing B, Liu C, Naji A, Ma X, Simmons RA, Hua X. Menin and PRMT5 suppress GLP1 receptor transcript and PKA-mediated phosphorylation of FOXO1 and CREB. Am J Physiol Endocrinol Metab 2017; 313:E148-E166. [PMID: 28270438 PMCID: PMC5582886 DOI: 10.1152/ajpendo.00241.2016] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 01/11/2017] [Accepted: 02/20/2017] [Indexed: 12/23/2022]
Abstract
Menin is a scaffold protein that interacts with several epigenetic mediators to regulate gene transcription, and suppresses pancreatic β-cell proliferation. Tamoxifen-inducible deletion of multiple endocrine neoplasia type 1 (MEN1) gene, which encodes the protein menin, increases β-cell mass in multiple murine models of diabetes and ameliorates diabetes. Glucagon-like-peptide-1 (GLP1) is another key physiological modulator of β-cell mass and glucose homeostasis. However, it is not clearly understood whether menin crosstalks with GLP1 signaling. Here, we show that menin and protein arginine methyltransferase 5 (PRMT5) suppress GLP1 receptor (GLP1R) transcript levels. Notably, a GLP1R agonist induces phosphorylation of forkhead box protein O1 (FOXO1) at S253, and the phosphorylation is mediated by PKA. Interestingly, menin suppresses GLP1-induced and PKA-mediated phosphorylation of both FOXO1 and cAMP response element binding protein (CREB), likely through a protein arginine methyltransferase. Menin-mediated suppression of FOXO1 and CREB phosphorylation increases FOXO1 levels and suppresses CREB target genes, respectively. A small-molecule menin inhibitor reverses menin-mediated suppression of both FOXO1 and CREB phosphorylation. In addition, ex vivo treatment of both mouse and human pancreatic islets with a menin inhibitor increases levels of proliferation marker Ki67. In conclusion, our results suggest that menin and PRMT5 suppress GLP1R transcript levels and PKA-mediated phosphorylation of FOXO1 and CREB, and a menin inhibitor may reverse this suppression to induce β-cell proliferation.
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Affiliation(s)
- Abdul Bari Muhammad
- Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Institute for Diabetes, Obesity, and Metabolism Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Bowen Xing
- Shenzen University School of Medicine, Institute of Diabetes Research, Shenzhen, Guangdong, China
| | - Chengyang Liu
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ali Naji
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Institute for Diabetes, Obesity, and Metabolism Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Xiaosong Ma
- Shenzen University School of Medicine, Institute of Diabetes Research, Shenzhen, Guangdong, China
| | - Rebecca A Simmons
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and
- Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Xianxin Hua
- Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania;
- Institute for Diabetes, Obesity, and Metabolism Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Luzi E, Marini F, Ciuffi S, Galli G, Brandi ML. An autoregulatory network between menin and pri-miR-24-1 is required for the processing of its specific modulator miR-24-1 in BON1 cells. MOLECULAR BIOSYSTEMS 2017; 12:1922-8. [PMID: 27098433 DOI: 10.1039/c6mb00118a] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary cancer complex syndrome manifesting a variety of endocrine and non-endocrine neoplasms and lesions. MEN1 is characterized by tumours of the parathyroids, of the neuroendocrine cells of the gastroenteropancreatic tract, and of the anterior pituitary. The MEN1 gene, a tumour suppressor gene, encodes the menin protein. Loss of heterozygosity (LOH) at 11q13 is typical of MEN1 tumours in agreement with Knudson's two-hit hypothesis. We previously showed that the MEN1 parathyroid tumorigenesis is under the control of an "incoherent feedback loop" between miR-24-1 and the menin protein that generates a "Gene Regulatory Network" (GRN) that mimics the second hit of Knudson's hypothesis and that could buffer the effect of the stochastic factors that contribute to the onset and progression of this disease. Here we show, in the BON1 cell line derived from lymphnode metastasis of a human carcinoid tumour of the pancreas, that menin binds specifically to the primary RNA sequence pri-miR-24-1 by promoting the miR-24-1 biogenesis. Network simulation showed a new feed-forward loop between menin, microRNA-24-1 and Musashi-1 proteins. This result shows a novel mechanism whereby menin, a RNA-binding protein, facilitates the processing of its specific miRNA by regulating the dynamics of the menin-miR-24 Gene Regulatory Network at the level of pri-miRNA processing.
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Affiliation(s)
- Ettore Luzi
- Department of Surgery and Translational Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
| | - Francesca Marini
- Department of Surgery and Translational Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
| | - Simone Ciuffi
- Department of Surgery and Translational Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
| | - Gianna Galli
- Department of Surgery and Translational Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
| | - Maria Luisa Brandi
- Department of Surgery and Translational Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
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Petkevicius V, Salteniene V, Juzenas S, Wex T, Link A, Leja M, Steponaitiene R, Skieceviciene J, Kupcinskas L, Jonaitis L, Kiudelis G, Malfertheiner P, Kupcinskas J. Polymorphisms of microRNA target genes IL12B, INSR, CCND1 and IL10 in gastric cancer. World J Gastroenterol 2017; 23:3480-3487. [PMID: 28596683 PMCID: PMC5442083 DOI: 10.3748/wjg.v23.i19.3480] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Revised: 02/23/2017] [Accepted: 03/21/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate associations between miRNA target genes IL12B, INSR, CCND1 and IL10 polymorphisms and gastric cancer (GC) in European population. METHODS Gene polymorphisms were analyzed in 508 controls and 474 GC patients from 3 tertiary centers in Germany, Lithuania and Latvia. Controls were patients from the out-patient departments, who were referred for upper endoscopy because of dyspeptic symptoms and had no history of previous malignancy. Gastric cancer (GC) patients had histopathological verification of gastric adenocarcinoma. Genomic DNA was extracted using salting out method from peripheral blood mononuclear cells. IL12B T>G (rs1368439), INSR T>C (rs1051690), CCND1 A>C (rs7177) and IL10 T>C (rs3024498) SNPs were genotyped by the real-time polymerase chain reaction. Associations between gene polymorphism and GC were evaluated using multiple logistic regression analysis with adjustment for sex, age and country of birth. RESULTS We observed similar distribution of genotypes and allelic frequencies of all polymorphisms between GC patients and controls except of INSR rs1051690. The frequency of the T allele of INSR gene was significantly higher in GC patients than in controls (23.26% and 19.19% respectively, P = 0.028). CT genotype was also more prevalent in patients compared to control group (38.48% and 30.12% respectively, P < 0.021). Logistic regression analysis revealed that only one polymorphism (rs1051690 in INSR gene) was associated with increased risk of GC. Carriers of CT genotype had higher odds of GC when compared to CC genotype (OR = 1.45, 95%PI: 1.08-1.95, P = 0.01). Similar association was observed in a dominant model for INSR gene, where comparison of TT+CT vs CC genotypes showed an increased risk of GC (OR = 1.44, 95%PI: 1.08-1.90, P = 0.01). Other analyzed SNPs were not associated with the presence of GC. CONCLUSION INSR rs1051690 SNP is associated with increased risk of GC, while polymorphisms in IL12B, CCND1 and IL10 genes are not linked with the presence of GC.
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11
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Eliasson L, Esguerra JLS, Wendt A. Lessons from basic pancreatic beta cell research in type-2 diabetes and vascular complications. Diabetol Int 2017; 8:139-152. [PMID: 30603317 DOI: 10.1007/s13340-017-0304-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 01/08/2017] [Indexed: 12/14/2022]
Abstract
The changes in life-style with increased access of food and reduced physical activity have resulted in the global epidemic of obesity. Consequently, individuals with type 2 diabetes and cardiovascular disease have also escalated. A central organ in the development of diabetes is the pancreas, and more specifically the pancreatic beta cells within the islets of Langerhans. Beta cells have been assigned the important task of secreting insulin when blood glucose is increased to lower the glucose level. An early sign of diabetes pathogenesis is lack of first phase insulin response and reduced second phase secretion. In this review, which is based on the foreign investigator award lecture given at the JSDC meeting in Sendai in October 2016, we discuss a possible cellular explanation for the reduced first phase insulin response and how this can be influenced by lipids. Moreover, since patients with cardiovascular disease and high levels of cholesterol are often treated with statins, we summarize recent data regarding effects on statins on glucose homeostasis and insulin secretion. Finally, we suggest microRNAs (miRNAs) as central players in the adjustment of beta cell function during the development of diabetes. We specifically discuss miRNAs regarding their involvement in insulin secretion regulation, differential expression in type 2 diabetes, and potential as biomarkers for prediction of diabetes and cardiovascular complications.
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Affiliation(s)
- Lena Eliasson
- Islet Cell Exocytosis, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Lund University, Clinical Research Centre, SUS 91-11, Box 50332, 202 13 Malmö, Sweden
| | - Jonathan Lou S Esguerra
- Islet Cell Exocytosis, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Lund University, Clinical Research Centre, SUS 91-11, Box 50332, 202 13 Malmö, Sweden
| | - Anna Wendt
- Islet Cell Exocytosis, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, Lund University, Clinical Research Centre, SUS 91-11, Box 50332, 202 13 Malmö, Sweden
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12
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Dalgaard LT, Eliasson L. An 'alpha-beta' of pancreatic islet microribonucleotides. Int J Biochem Cell Biol 2017; 88:208-219. [PMID: 28122254 DOI: 10.1016/j.biocel.2017.01.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Revised: 01/16/2017] [Accepted: 01/18/2017] [Indexed: 11/17/2022]
Abstract
MicroRNAs (miRNAs) are cellular, short, non-coding ribonucleotides acting as endogenous posttranscriptional repressors following incorporation in the RNA-induced silencing complex. Despite being chemically and mechanistically very similar, miRNAs exert a multitude of different cellular effects by acting on mRNA species, whose gene-products partake in a wide array of processes. Here, the aim was to review the knowledge of miRNA expression and action in the islet of Langerhans. We have focused on: 1) physiological consequences of islet or beta cell specific inhibition of miRNA processing, 2) mechanisms regulating processing of miRNAs in islet cells, 3) presence and function of miRNAs in alpha versus beta cells - the two main cell types of islets, and 4) miRNA mediators of beta cell decompensation. It is clear that miRNAs regulate pancreatic islet development, maturation, and function in vivo. Moreover, processing of miRNAs appears to be altered by obesity, diabetes, and aging. A number of miRNAs (such as miR-7, miR-21, miR-29, miR-34a, miR-212/miR-132, miR-184, miR-200 and miR-375) are involved in mediating beta cell dysfunction and/or compensation induced by hyperglycemia, oxidative stress, cytotoxic cytokines, and in rodent models of fetal metabolic programming prediabetes and overt diabetes. Studies of human type 2 diabetic islets underline that these miRNA families could have important roles also in human type 2 diabetes. Furthermore, there is a genuine gap of knowledge regarding miRNA expression and function in pancreatic alpha cells. Progress in this area would be enhanced by improved in vitro alpha cell models and better tools for islet cell sorting.
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Affiliation(s)
| | - Lena Eliasson
- Lund University Diabetes Center, Department of Clinical Sciences Malmö, CRC, SUS, Malmö, Sweden.
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13
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Hashimoto N, Tanaka T. Role of miRNAs in the pathogenesis and susceptibility of diabetes mellitus. J Hum Genet 2016; 62:141-150. [PMID: 27928162 DOI: 10.1038/jhg.2016.150] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 10/23/2016] [Accepted: 11/04/2016] [Indexed: 12/16/2022]
Abstract
MicroRNAs (miRNAs) are noncoding RNAs of ~22 nucleotides that regulate gene expression post-transcriptionally by binding to the 3' untranslated region of messenger RNA (mRNAs), resulting in inhibition of translation or mRNA degradation. miRNAs have a key role in fine-tuning cellular functions such as proliferation, differentiation and apoptosis, and they are involved in carcinogenesis, glucose homeostasis, inflammation and other biological processes. In this review, we focus on the role of miRNAs in the pathophysiology of the metabolic disease and diabetes mellitus, the hallmark of which is hyperglycemia caused by defective insulin secretion and/or action. A growing number of studies have revealed the association between miRNAs and the processes of insulin production and secretion in pancreatic β cells. In addition, aberrant expression of miRNAs in skeletal muscle, adipose tissue and liver has also been reported. Intriguingly, the tumor suppressor p53 has been implicated in the pathogenesis of diabetes in association with a number of miRNAs, suggesting that a p53/miRNA pathway might be a therapeutic target. Moreover, data from genome-wide association studies have revealed that several miRNA target sequences overlap type 2 diabetes susceptibility loci. Finally, the recent discovery of circulating miRNAs associated with diabetes onset/progression suggests the potential use of miRNAs as biomarkers.
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Affiliation(s)
- Naoko Hashimoto
- Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.,Division of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, Japan.,AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan
| | - Tomoaki Tanaka
- Division of Diabetes, Endocrinology and Metabolism, Chiba University Hospital, Chiba, Japan.,AMED-CREST, AMED, Japan Agency for Medical Research and Development, Tokyo, Japan.,Department of Molecular Diagnosis, Graduate School of Medicine, Chiba University, Chiba, Japan
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14
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Dumortier O, Fabris G, Van Obberghen E. Shaping and preserving β-cell identity with microRNAs. Diabetes Obes Metab 2016; 18 Suppl 1:51-7. [PMID: 27615131 DOI: 10.1111/dom.12722] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 05/26/2016] [Indexed: 12/18/2022]
Abstract
The highly sophisticated identity of pancreatic β-cells is geared to accomplish its unique feat of providing insulin for organismal glucose and lipid homeostasis. This requires a particular and streamlined fuel metabolism which defines mature β-cells as glucose sensors linked to an insulin exocytosis machinery. The establishment of an appropriate β-cell mass and function during development as well as the maintenance of their identity throughout life are necessary for energy homeostasis. The small non-coding RNAs, microRNAs (miRNAs), are now well-recognized regulators of gene transcripts, which in general are negatively affected by them. Convincing evidence exists to view miRNAs as major actors in β-cell development and function, suggesting an important role for them in the distinctive β-cell 'identity card'. Here, we summarize key features that associate miRNAs and the establishment of the appropriate β-cell identity and its necessary maintenance during their 'long life'.
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Affiliation(s)
- O Dumortier
- University Côte d'Azur, Inserm, CNRS, IRCAN, France
| | - G Fabris
- University Côte d'Azur, Inserm, CNRS, IRCAN, France
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15
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Abstract
Noncoding RNA and especially microRNAs (miRs) have emerged as important regulators of key processes in cell biology, including development, differentiation, and survival. Currently, over 2,500 mature miRs have been reported in humans, and considering that each miR has multiple targets, the number of genes and pathways potentially affected is huge. Not surprisingly, many miRs have also been implicated in diabetes, and more recently, some have been discovered to play important roles in the pancreatic islet, including β-cell function, proliferation, and survival. The goal of this Perspective is to offer an overview of this rapidly evolving field and the miRs involved, reveal novel networks of β-cell miR signaling, and provide an outlook of the opportunities and challenges ahead.
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Affiliation(s)
- Stephen R Filios
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, The University of Alabama at Birmingham, Birmingham, AL
| | - Anath Shalev
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, The University of Alabama at Birmingham, Birmingham, AL
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16
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Briggs CE, Wang Y, Kong B, Woo TUW, Iyer LK, Sonntag KC. Midbrain dopamine neurons in Parkinson's disease exhibit a dysregulated miRNA and target-gene network. Brain Res 2015; 1618:111-121. [PMID: 26047984 PMCID: PMC4522231 DOI: 10.1016/j.brainres.2015.05.021] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Revised: 05/09/2015] [Accepted: 05/15/2015] [Indexed: 11/21/2022]
Abstract
The degeneration of substantia nigra (SN) dopamine (DA) neurons in sporadic Parkinson׳s disease (PD) is characterized by disturbed gene expression networks. Micro(mi)RNAs are post-transcriptional regulators of gene expression and we recently provided evidence that these molecules may play a functional role in the pathogenesis of PD. Here, we document a comprehensive analysis of miRNAs in SN DA neurons and PD, including sex differences. Our data show that miRNAs are dysregulated in disease-affected neurons and differentially expressed between male and female samples with a trend of more up-regulated miRNAs in males and more down-regulated miRNAs in females. Unbiased Ingenuity Pathway Analysis (IPA) revealed a network of miRNA/target-gene associations that is consistent with dysfunctional gene and signaling pathways in PD pathology. Our study provides evidence for a general association of miRNAs with the cellular function and identity of SN DA neurons, and with deregulated gene expression networks and signaling pathways related to PD pathogenesis that may be sex-specific.
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Affiliation(s)
- Christine E Briggs
- The Center of Cancer Systems Biology, Tufts University School of Medicine, Boston, MA 02135, USA
| | - Yulei Wang
- Life Technologies, Foster City, CA 94404, USA
| | | | - Tsung-Ung W Woo
- Department of Psychiatry, McLean Hospital, Harvard Medical School, MRC 223, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA
| | - Lakshmanan K Iyer
- Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02135, USA
| | - Kai C Sonntag
- Department of Psychiatry, McLean Hospital, Harvard Medical School, MRC 223, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
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17
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Verdelli C, Forno I, Vaira V, Corbetta S. MicroRNA deregulation in parathyroid tumours suggests an embryonic signature. J Endocrinol Invest 2015; 38:383-8. [PMID: 25577262 DOI: 10.1007/s40618-014-0234-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Accepted: 12/20/2014] [Indexed: 12/22/2022]
Abstract
Primary hyperparathyroidism is a common endocrine disorder caused by abnormal tumour parathyroid cell proliferation. Parathyroid tumours show a great variability both in clinical features, such as the severity of PTH secretion, the rate and the pattern of cell proliferation, and genetic background. Studies aiming to develop new diagnostic markers and therapeutic approaches need a deeper definition of this variability. Dysregulation of microRNAs (miRNAs) has been shown to play an essential role in the development and progression of cancer. MiRNAs are small noncoding RNAs that inhibit the translation and stability of messenger RNAs (mRNAs). Here, data about the miRNA expression pattern in parathyroid normal and tumour glands were reviewed. Though available data in parathyroid tumours are very limited, the expression pattern of a subset of specific miRNAs clearly discriminated parathyroid carcinomas from normal parathyroid glands and, more clinically relevant, from parathyroid adenomas. Investigation showed that parathyroid tumours were characterized by an embryonic expression pattern of miRNAs such as miR-296, or the miRNA clusters C19MC and miR-371-3, typically in stem cells committed to differentiation or during human embryonic development, respectively. Further, miRNA profiles were correlated with tumour aggressive behaviour. Moreover, the interaction with the oncosuppressor menin suggests that miRNAs might modulate the function of the known oncosuppressors or oncogenes involved in parathyroid tumourigenesis and thus overseeing the tumour phenotype. In conclusion, miRNAs might provide new diagnostic markers and new therapeutic approaches by developing molecular miRNA-targeted therapies for the cure of parathyroid tumours, whose unique option is surgery.
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Affiliation(s)
- C Verdelli
- Laboratory of Molecular Biology, IRCCS Policlinico San Donato, San Donato Milanese, MI, Italy
| | - I Forno
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - V Vaira
- Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - S Corbetta
- Endocrinology and Diabetology Unit, Department of Biomedical Sciences, University of Milan, IRCCS Policlinico San Donato, Via Morandi 30, 20097, San Donato Milanese, MI, Italy.
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18
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Zou T, Rao JN, Liu L, Xiao L, Chung HK, Li Y, Chen G, Gorospe M, Wang JY. JunD enhances miR-29b levels transcriptionally and posttranscriptionally to inhibit proliferation of intestinal epithelial cells. Am J Physiol Cell Physiol 2015; 308:C813-24. [PMID: 25788572 DOI: 10.1152/ajpcell.00027.2015] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 03/14/2015] [Indexed: 12/28/2022]
Abstract
Through its actions as component of the activating protein-1 (AP-1) transcription factor, JunD potently represses cell proliferation. Here we report a novel function of JunD in the regulation of microRNA expression in intestinal epithelial cells (IECs). Ectopically expressed JunD specifically increased the expression of primary and mature forms of miR-29b, whereas JunD silencing inhibited miR-29b expression. JunD directly interacted with the miR-29b1 promoter via AP-1-binding sites, whereas mutation of AP-1 sites from the miR-29b1 promoter prevented JunD-mediated transcriptional activation of the miR-29b1 gene. JunD also enhanced formation of the Drosha microprocessor complex, thus further promoting miR-29b biogenesis. Cellular polyamines were found to regulate miR-29b expression by altering JunD abundance, since the increase in miR-29b expression levels in polyamine-deficient cells was abolished by JunD silencing. In addition, miR-29b silencing prevented JunD-induced repression of IEC proliferation. Our findings indicate that JunD activates miR-29b by enhancing its transcription and processing, which contribute to the inhibitory effect of JunD on IEC growth and maintenance of gut epithelium homeostasis.
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Affiliation(s)
- Tongtong Zou
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Jaladanki N Rao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Lan Liu
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Lan Xiao
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Hee Kyoung Chung
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Yanwu Li
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Gang Chen
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, Maryland; and
| | - Jian-Ying Wang
- Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland; Baltimore Veterans Affairs Medical Center, Baltimore, Maryland; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland
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Menin-mediated regulation of miRNA biogenesis uncovers the IRS2 pathway as a target for regulating pancreatic beta cells. Oncoscience 2014; 1:562-6. [PMID: 25594065 PMCID: PMC4278340 DOI: 10.18632/oncoscience.79] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 09/08/2014] [Indexed: 01/20/2023] Open
Abstract
Menin, a protein encoded by the MEN1 gene, is mutated in patients with multiple endocrine neoplasia type 1 (MEN1). Menin acts as a tumor suppressor in endocrine organs while it is also required for transformation of a subgroup of leukemia. The recently solved crystal structure of menin with different binding partners reveals that menin is a key scaffold protein that cross-talks with various partners, including transcription factors, to regulate gene transcription. Our recent findings unravel a previously undiscovered mechanism for menin-mediated control of gene expression via processing of certain microRNA's, thus adding to the plethora of ways in which menin regulates gene expression. By interacting with ARS2, an RNA binding protein, menin facilitates the processing of pri-let 7a and pri-miR155 to pre-let 7a and pre-miR155 respectively. Consistently, excision of the Men1 gene results in upregulation of IRS2, a let-7a target. As IRS2 is known to mediate both insulin signaling and insulin-induced cell proliferation, and let-7a targets include oncogenes like RAS and HMGA2, a deeper understanding of the menin-ARS2 complex in regulating miRNA biogenesis will yield further insights into the pathogenesis of the MEN1 syndrome and other menin-associated malignancies.
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MicroRNA-142-3p, a novel target of tumor suppressor menin, inhibits osteosarcoma cell proliferation by down-regulation of FASN. Tumour Biol 2014; 35:10287-93. [DOI: 10.1007/s13277-014-2316-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 07/04/2014] [Indexed: 10/25/2022] Open
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