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1
Huang, Yu-Qing, Jie Li, Cheng Huang, and Ying-Qing Feng. "Plasma MicroRNA-29c Levels Are Associated with Carotid Intima-Media Thickness and is a Potential Biomarker for the Early Detection of Atherosclerosis." Cellular Physiology and Biochemistry 50, no. 2 (2018): 452–59. http://dx.doi.org/10.1159/000494158.
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Background/Aims: Atherosclerosis is a serious disease that increases the risk of myocardial infarction and ischemic stroke. Previous studies have demonstrated that microRNA (miR)-29c could play significant roles in atherosclerosis via regulating inflammatory processes. However, the relationship between miR-29c and carotid intima-media thickness (CIMT) remains unknown. This study investigated associations between miR-29c and atherosclerosis and tested whether plasma miR-29c levels could be used to detect atherosclerosis. Methods: Plasma miR-29c levels were estimated by quantitative real-time PCR, and CIMT was measured by carotid ultrasound. Associations between miR-29c and CIMT were assessed by Spearman’s correlation coefficient and multiple linear regression analyses. Results: In total, 170 participants were divided into the study (CIMT ≥0.9 mm) and control (CIMT < 0.9 mm) groups. The study group showed higher C-reactive protein (CRP) and miR-29c relative expression levels compared with the control group. CIMT was positively correlated with miR-29c (r=0.659, p< 0.001) and CRP (r=0.447, p< 0.001), and miR-29c levels were also correlated with CRP (r=0.512, p< 0.001). Furthermore, multiple linear regression analysis showed that CIMT was significantly correlated with miR-29c (β=0.573, 95% confidence interval [CI]: 0.315-0.839; p< 0.001) and CRP (β=0.439, 95%CI: 0.186–0.825; p< 0.001). After age, body mass index, systolic blood pressure, total cholesterol and fasting blood-glucose were adjusted for, CIMT was still closely associated with miR-29c (β=0.529, 95%CI: 0.354–0.812; p< 0.001) and CRP (β=0.417, 95%CI: 0.198–0.724; p< 0.001). Evaluating CRP and miR-29c together (AUC=0.900, p< 0.001) achieved a better prognostic value for atherosclerosis than miR-29c (AUC=0.870, p< 0.001) or CRP (AUC=0.722, p< 0.001) alone. Conclusion: Increased miR-29c was closely associated with CIMT and may serve as a biomarker for identifying atherosclerotic patients.
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Liu, Jiazheng, Guilu Tao, Cundi Zhong, and Xiao Liu. "Upregulation of miR-29c-3p Hinders Melanoma Progression by Inhibiting CDCA4 Expression." BioMed Research International 2021 (August 28, 2021): 1–15. http://dx.doi.org/10.1155/2021/7065963.
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Objective. To investigate the expression and regulation mechanism of miR-29c-3p and cell division cycle associated 4 (CDCA4) in melanoma (MM). Data and Methods. Fifty-nine patients with MM admitted to our hospital were enrolled as the MM group. They were followed up for 3 years to analyze the prognostic factors; meanwhile, 51 healthy subjects were allocated into a normal group. MM cell lines (M21 and C8161) were transfected with miR-29c-3p-mimics, miR-29c-3p-inhibitor, miR-NC, si-CDCA4, and sh-CDCA4. The expression of miR-29c-3p, CDCA4, Bax, Caspase3, Bcl-2, N-cadherin, vimentin, and E-cadherin was quantified, and cell proliferation, migration, invasion, and apoptosis, as well as epithelial-mesenchymal transition (EMT), were determined. Results. Serum miR-29c-3p was lowly expressed and CDCA4 was highly expressed in the MM group. The area under the curve (AUC) of both for diagnosing MM was greater than 0.9. miR-29c-3p and CDCA4 were related to regional lymph node staging (N staging), distant metastasis (M staging), tumor diameter, and pathological differentiation. Low miR-29c-3p and high CDCA4 were associated with poor prognosis of MM. Overexpression of miR-29c-3p and suppression of CDCA4 hindered cell proliferation, migration, invasion, and expression of Bax, Caspase3, N-cadherin, and vimentin, but cell apoptosis and expression of Bcl-2 and E-cadherin were enhanced. Dual-luciferase reporter (DLR) assay confirmed the targeted relationship between miR-29c-3p and CDCA4. After miR-29c-3p-mimics+sh-CDCA4 was transfected into M21 and C8161 cells, the proliferation, invasion, and apoptosis were not different from those in the miR-NC group transfected with unrelated sequences. Conclusion. Overexpression of miR-29c-3p suppresses CDCA4 expression and decreases proliferation, migration, invasion, apoptosis, and EMT of MM cells, thus hindering MM progression.
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Cao, Yanqun, Xiangxiang Tan, Quzhe Lu, Kai Huang, Xiaoer Tang, and Zhiming He. "MiR-29c-3p May Promote the Progression of Alzheimer’s Disease through BACE1." Journal of Healthcare Engineering 2021 (December 15, 2021): 1–11. http://dx.doi.org/10.1155/2021/2031407.
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The aim of this study was to explore the specific role of miR-29c-3p in Alzheimer’s disease (AD). Animal models of AD were established by injecting streptozotocin (STZ) into mice through the lateral ventricle, while cell models of AD were induced by 10 μM β-amyloid (Aβ). We detected miR-29c-3p and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) contents and measured AD cell proliferation and apoptosis. A low miR-29c-3p level and a high BACE1 level were detected in the brain tissue of AD animal models and AD cell models. Aβ-processed cells had markedly lower proliferation activity, higher apoptosis, increased phosphorylation of tau protein was over phosphorylated, but the overexpression of miR-29c-3p or the silencing of BACE1 significantly enhanced the cell proliferation activity and reduced cell apoptosis by regulating the contents of related proteins. Inhibition of miR-29c-3p or overexpression of BACE1 aggravated Aβ-induced side effects. We used Targetscan7.2 to predict the downstream target genes of miR-29c-3p. Then, we detected that there were target binding sites between miR-29c-3p and BACE1. The rescue experiment identified BACE1 as a functional target for miR-29c-3p. AD leads to decreased miR-29c-3p level and increased BACE1 level. MiR-29c-3p has specific binding sites with the 3′-untranslated region (3′-UTR) of BACE1 and thus negatively regulates the BACE1 level, thereby affecting the progression of AD.
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Wang, Shaoqiang, Pengfei Yi, Na Wang, Min Song, Wenhui Li, and Yingying Zheng. "LncRNA TUG1/miR-29c-3p/SIRT1 axis regulates endoplasmic reticulum stress-mediated renal epithelial cells injury in diabetic nephropathy model in vitro." PLOS ONE 16, no. 6 (June 7, 2021): e0252761. http://dx.doi.org/10.1371/journal.pone.0252761.
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Long non-coding RNAs (lncRNAs) are important regulators in diabetic nephropathy. In this study, we investigated the potential role of lncRNA TUG1 in regulating endoplasmic reticulum stress (ERS)-mediated apoptosis in high glucose induced renal tubular epithelial cells. Human renal tubular epithelial cell line HK-2 was challenged with high glucose following transfection with lncRNA TUG1, miR-29c-3p mimics or inhibitor expression plasmid, either alone or in combination, for different experimental purposes. Potential binding effects between TUG1 and miR-29c-3p, as well as between miR-29c-3p and SIRT1 were verified. High glucose induced apoptosis and ERS in HK-2 cells, and significantly decreased TUG1 expression. Overexpressed TUG1 could prevent high glucose-induced apoptosis and alleviated ERS via negatively regulating miR-29c-3p. In contrast, miR-29c-3p increased HK-2 cells apoptosis and ERS upon high glucose-challenge. SIRT1 was a direct target gene of miR-29c-3p in HK-2 cells, which participated in the effects of miR-29c-3p on HK-2 cells. Mechanistically, TUG1 suppressed the expression of miR-29c-3p, thus counteracting its function in downregulating the level of SIRT1. TUG1 regulates miR-29c-3p/SIRT1 and subsequent ERS to relieve high glucose induced renal epithelial cells injury, and suggests a potential role for TUG1 as a promising diagnostic marker of diabetic nephropathy.
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Dai, Qijun, Jian Sun, Tianyi Dai, Qin Xu, and Yueqin Ding. "miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6." Open Medicine 17, no. 1 (January 1, 2022): 353–64. http://dx.doi.org/10.1515/med-2022-0438.
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Abstract Blood–brain barrier participates in the pathological process of ischemic stroke. MicroRNA-29c-5p was highly expressed in clinical samples from patients with ischemic stroke. In this study, oxygen-glucose deprivation (OGD) treatment of astrocytes enhanced the permeability of brain microvascular endothelial cells (BMECs), and the miR-29c-5p expression was elevated in clinical samples from patients with ischemic stroke. For the function of miR-29c-5p in ischemic stroke, the miR-29c-5p knockdown decreased the permeability and the tight junction protein (TJP) destruction of BMECs and ameliorated the inflammation induced by OGD-treated astrocytes. Mechanistically, miR-29c-5p interacted with lipoprotein receptor-related protein 6 (LRP6) and negatively regulated the LRP6 expression in astrocytes. Moreover, the rescue assays indicated that the interference with miR-29c-5p ameliorated the TJP destruction of BMECs and inflammation caused by OGD-treated astrocytes by increasing the LRP6 expression. Together, miR-29c-5p knockdown decreased the high permeability and the TJP destruction of BMECs and ameliorated the inflammation induced by OGD-treated astrocytes by elevating LRP6 expression.
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Wang, X., K. Xu, XY Yang, J. Liu, Q. Zeng, and FS Wang. "Upregulated miR-29c suppresses silica-induced lung fibrosis through the Wnt/β-catenin pathway in mice." Human & Experimental Toxicology 37, no. 9 (December 8, 2017): 944–52. http://dx.doi.org/10.1177/0960327117741750.
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Silicosis is an irreversible lung disease resulting from long-term inhalation of occupational dust containing silicon dioxide. However, the pathogenesis of silicosis has not been clearly understood yet. Accumulating evidence suggests that miR-29 may have a significant anti-fibrotic capacity, meanwhile it may relate to Wnt/β-catenin pathway. The purpose of this study was to discuss the role of miR-29 in the progression of silicosis. A lentiviral vector was constructed, named Lv-miR-29c, which was overexpressing miR-29c. In vivo, intratracheal treatment with Lv-miR-29c significantly increased expression of miR-29c, and reduced expression of β-catenin, matrix metalloproteinase (MMP)-2, and MMP-9 in the lung and levels of transforming growth factor-beta 1 (TGF-β1) and interleukin-6 (IL-6) in bronchoalveolar lavage fluid, and notably attenuated pulmonary fibrosis as evidenced by hydroxyproline content in silica-administered mice. These results indicated that miR-29c inhibited the development of silica-induced lung fibrosis. Thus, miR-29c may be a candidate target for silicosis treatment via its regulation of the Wnt/β-catenin pathway.
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Fang, Yi, Xiaofang Yu, Yong Liu, Alison J. Kriegel, Yanyan Heng, Xialian Xu, Mingyu Liang, and Xiaoqiang Ding. "miR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by HIF-α activation." American Journal of Physiology-Renal Physiology 304, no. 10 (May 15, 2013): F1274—F1282. http://dx.doi.org/10.1152/ajprenal.00287.2012.
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Treatment with l-mimosine, which activates hypoxia-inducible factor-α (HIF-α), attenuates renal tubulointerstitial injury and improves renal function in a rat remnant kidney model. The miR-29 family of microRNAs directly targets a large number of extracellular matrix genes and reduces renal interstitial fibrosis. We analyzed microRNA expression profiles in rat remnant kidneys with or without treatment with l-mimosine. The expression of miR-29c was downregulated in rat remnant kidneys compared with sham control and significantly restored by the l-mimosine treatment. In cultured human kidney epithelial HK2 cells, cobalt chloride activated HIF-α and upregulated miR-29c expression. The upregulation of miR-29c expression was significantly attenuated by knockdown of HIF-1α or HIF-2α. Downregulation of miR-29c was associated with significant increases in interstitial fibrosis, collagen type II α1 (COL2A1) protein, and tropomyosin 1α (TPM1) protein in rat remnant kidneys and in kidneys from IgA nephropathy patients. The increases in rat remnant kidneys were attenuated by the l-mimosine treatment. COL2A1 and TPM1 were confirmed to be new, direct targets of miR-29c. In conclusion, miR-29c, an antifibrotic microRNA, is upregulated by HIF-α activation. MiR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by activation of HIF-α that attenuates fibrosis.
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Chuang, Tsai-Der, William J. Pearce, and Omid Khorram. "miR-29c induction contributes to downregulation of vascular extracellular matrix proteins by glucocorticoids." American Journal of Physiology-Cell Physiology 309, no. 2 (July 15, 2015): C117—C125. http://dx.doi.org/10.1152/ajpcell.00254.2014.
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Maternal undernutrition increases maternal glucocorticoids (GCs) and alters microRNA expression in offspring. Given that the mechanisms of GC action on vascular development are not clear, this study examined the influence of GCs on microRNA 29c (miR-29c) and its predicted targets in primary rat aorta smooth muscle cells (RAOSMCs). Dexamethasone (Dex) and corticosterone (Cor) time-dependently increased miR-29c expression and reduced collagen type III (Col3A1), collagen type IV (Col4A5), elastin (ELN), and matrix metalloproteinase-2 (MMP2) protein in RAOSMCs. These effects were blocked by mifepristone. These genes were also targeted by miR-29c, as confirmed by a significant decrease in luciferase reporter activity of Col3A1 (34%), Col4A5 (45%), ELN (17%), and MMP2 (28%). In cells transfected with reporter plasmids, including the 3′-untranslated region of genes targeted by miR-29c, treatment with Dex or Cor also resulted in decreases in luciferase activity. Gain or loss of function of miR-29c significantly altered mRNA expression of Col3A1 (26% and 26%, respectively), Col4A5 (28% and 32%, respectively), and MMP2 (24% and 14%, respectively) but did not affect ELN. Gain or loss of function of miR-29c also significantly altered protein levels of Col3A1 (51% and 16%, respectively), Col4A5 (56% and 22%, respectively), ELN (53% and 71%, respectively), and MMP2 (28% and 53%, respectively). Coincubation of anti-miR-29c with Dex or Cor partially attenuated the effects of these steroids on protein expression of Col3A1 (25% and 24%, respectively), Col4A5 (26% and 44%, respectively), ELN (31% and 55%, respectively), and MMP2 (46% and 26%, respectively) in RAOSMCs compared with anti-miR negative controls. Our results demonstrate that GCs regulate the expression of Col3A1, Col4A5, ELN, and MMP2, at least in part, through induction of miR-29c.
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Batliner, Jasmin, Mathias Jenal, Martin F. Fey, and Mario P. Tschan. "Mir-29c and Mir-424 Are Novel Myeloid Differentiation-Associated MicroRNAs in Acute Promyelocytic Leukemia." Blood 112, no. 11 (November 16, 2008): 3346. http://dx.doi.org/10.1182/blood.v112.11.3346.3346.
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Abstract MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level. Recent studies showed that they are critically involved in hematopoietic differentiation and function by a coordinating multi-target repression of hematopoiesis-related genes. To identify miRNAs involved in the pathogenesis of acute promyelocytic leukemia (APL), characterized by the t(15;17) translocation, we performed TaqMan Low Density Array-based miRNA expression profiling on blast cells from an APL patient under all-trans retinoic acid (ATRA) treatment. Although recent reports investigated miRNA expression patterns in APL blast cells and cell lines subjected to ATRA in vitro, to our knowledge this is the first study that relies on cells from an APL patient treated with ATRA in vivo. Since the downregulation of the PML-RARA transcript cannot be assessed within a time period of a few days, we monitored effective ATRA treatment by measuring mRNA downregulation of the panleukemic marker Wilms’ tumor (WT)-1. WT1 mRNA levels decreased 64% and 92% at day 3 and 6 upon ATRAtherapy, respectively. Total RNA obtained at diagnosis and at days 3/6 following ATRA therapy were screened for expression patterns of 384 human miRNAs including two endogenous controls, RNU44 and RNU48, for normalization of miRNA expression. Since these controls were regulated upon ATRA treatment, we normalized miRNA expression to miR-93, which showed stable expression in our samples. Consistent with previous in vitro APL miRNA profiling data, the granulocyte-specific miR-223 was induced 6.6-fold at day 6 upon ATRA treatment. For further analysis, we focused on two hematopoietic lineage-specific miRNAs, miR-29c and miR-424 that have not yet been associated with neutrophil development. miR-29c and miR-424 were upregulated 6.5- and 6.0-fold at day 6 in response to ATRA, respectively. Induction of these miRNAs was confirmed by individual real-time RT-PCR assays. Moreover, expression of miR-29c and miR-424 was further investigated in NB4 and HT93 APL cell lines. In both cell lines, miR-424 was upregulated in response to ATRA similar to the patient samples, suggesting a role for miR-424 in granulocytic differentiation in addition to that described in macrophage development. miR-29c, however, showed an upregulation in HT93 but not in NB4 cells implying cell type specific regulation. Additionally, we tested the involvement of miR- 29c in macrophage differentiation of HL60 leukemic cells using phorbol 12-myristate 13-acetate (PMA) as a differentiating agent. Interestingly, miR-29c showed an 8.0- fold upregulation similar to an 8.7-fold induction of miR-424, a known target of the transcription factor PU.1 upon PMA treatment. Based on the similar regulation of miR-29c and miR-424 and the presence of several putative PU.1 binding elements in the miR-29c promoter, we are currently investigating whether miR-29c is a novel transcriptional target of PU.1. A confirmed target of miR-29c is the protein DNA methyltransferase (DNMT 3A and 3B), which is overexpressed in myeloid leukemias. Therefore, induction of miR-29c during myelopoiesis might be needed to target DNMT. In conclusion, we propose a novel association of miR-29c and miR-424 with ATRA-induced neutrophil differentiation.
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Huang, Limin, Chaoquan Hu, Hui Cao, Xiaoliang Wu, Rongpin Wang, He Lu, Hong Li, and Hui Chen. "MicroRNA-29c Increases the Chemosensitivity of Pancreatic Cancer Cells by Inhibiting USP22 Mediated Autophagy." Cellular Physiology and Biochemistry 47, no. 2 (2018): 747–58. http://dx.doi.org/10.1159/000490027.
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Background/Aims: Pancreatic cancer (PC) is an aggressive malignancy with a poor survival rate. Despite advances in the treatment of PC, the efficacy of therapy is limited by the development of chemoresistance. Here, we examined the role of microRNA-29c (miR-29c) and the involvement of autophagy and apoptosis in the chemoresistance of PC cells in vivo and in vitro. Methods: We employed qRT-PCR, western blot and immunofluorescence to examine the expression level of miR-29c, USP22 and autophagy relative protein. In addition, we used MTT assay to detect cell proliferation and transwell assay to measure migration and invasiveness. The apoptosis was determined using annexin V-FITC/PI apoptosis detection kit by flow cytometry. Luciferase reporter assays confirmed the relationship between USP22 and miR-29c. Results: miR-29c overexpression in the PC cell line PANC-1 enhanced the effect of gemcitabine on decreasing cell viability and inducing apoptosis and inhibited autophagy, as shown by western blotting, immunofluorescence staining, colony formation assays, and flow cytometry. Ubiquitin specific peptidase (USP)-22, a deubiquitinating enzyme known to induce autophagy and promote PC cell survival, was identified as a direct target of miR-29c. USP22 knockdown experiments indicated that USP22 suppresses gemcitabine-induced apoptosis by promoting autophagy, thereby increasing the chemoresistance of PC cells. Luciferase reporter assays confirmed that USP22 is a direct target of miR-29c. A xenograft mouse model demonstrated that miR-29c increases the chemosensitivity of PC in vivo by downregulating USP22, leading to the inhibition of autophagy and induction of apoptosis. Conclusions: Taken together, these findings reveal a potential mechanism underlying the chemoresistance of PC cells mediated by the regulation of USP22-mediated autophagy by miR-29c, suggesting potential targets and therapeutic strategies in PC.
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Tang, Haitao, Hongli Zhong, Wanqing Liu, Yi Wang, Yuan Wang, Liuqing Wang, Songtao Tang, and Huaqing Zhu. "Melatonin Alleviates Hyperglycemia-Induced Cardiomyocyte Apoptosis via Regulation of Long Non-Coding RNA H19/miR-29c/MAPK Axis in Diabetic Cardiomyopathy." Pharmaceuticals 15, no. 7 (July 2, 2022): 821. http://dx.doi.org/10.3390/ph15070821.
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Recent studies revealed that non-coding RNAs (ncRNAs) play a crucial role in pathophysiological processes involved in diabetic cardiomyopathy (DCM) that contribute to heart failure. The present study was designed to further investigate the anti-apoptotic effect of melatonin on cardiomyocytes in diabetic conditions, and to elucidate the potential mechanisms associated with ncRNAs. In animal models, we induced diabetes in SD rats by single intraperitoneal injection of streptozotocin (STZ) solution (55 mg/kg) at 18:00 in the evening, after a week of adaptive feeding. Our results indicate that melatonin notably alleviated cardiac dysfunction and cardiomyocyte apoptosis. In the pathological situation, lncRNA H19 level increased, along with a concomitant decrease in miR-29c level. Meanwhile, melatonin significantly downregulated lncRNA H19 and upregulated miR-29c levels. In our in vitro experiments, we treated H9c2 cells with high-concentration glucose medium (33 mM) to simulate the state of diabetes. It was verified that positive modulation of miR-29c and inhibition of lncRNA H19, as well as mitogen-activated protein kinase (MAPK) pathways, distinctly attenuated apoptosis in high-glucose-treated H9c2 cells. A luciferase activity assay was conducted to evaluate the potential target sites of miR-29c on lncRNA H19 and MAPK13. LncRNA H19 silencing significantly downregulated the expression of miR-29c target gene MAPK13 by inducing miR-29c expression. Most importantly, our results show that melatonin alleviated apoptosis by inhibiting lncRNA H19/MAPK and increasing miR-29c level. Our results elucidate a novel protective mechanism of melatonin on diabetic cardiomyocyte apoptosis, which involved the regulation of lncRNA H19/miR-29c and MAPK pathways, providing a promising strategy for preventing DCM in diabetic patients.
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Matsushima, Shingo, and Junichi Ishiyama. "MicroRNA-29c regulates apoptosis sensitivity via modulation of the cell-surface death receptor, Fas, in lung fibroblasts." American Journal of Physiology-Lung Cellular and Molecular Physiology 311, no. 6 (December 1, 2016): L1050—L1061. http://dx.doi.org/10.1152/ajplung.00252.2016.
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MicroRNAs play an important role in the development and progression of various diseases, such as idiopathic pulmonary fibrosis (IPF). Although the accumulation of aberrant fibroblasts resistant to apoptosis is a hallmark in IPF lungs, the mechanism regulating apoptosis susceptibility is not fully understood. Here, we investigated the role of miR-29, which is the most downregulated microRNA in IPF lungs and is also known as a regulator of extracellular matrix (ECM), in the mechanism of apoptosis resistance. We found that functional inhibition of miR-29c caused resistance to Fas-mediated apoptosis in lung fibroblasts. Furthermore, experiments using miR-29c inhibitor and miR-29c mimic revealed that miR-29c regulated expression of the death receptor, Fas, and formation of death-inducing signaling complex leading to extrinsic apoptosis. The representative profibrotic transforming growth factor (TGF)-β downregulated the expression of miR-29c as well as Fas receptor and conferred resistance to apoptosis. We also found that introduction of miR-29c mimic abrogated these TGF-β-induced phenotypes of Fas repression and apoptosis resistance. The results presented here suggest that downregulation of miR-29 observed in IPF lungs may be associated with the apoptosis-resistant phenotype of IPF lung fibroblasts via downregulation of Fas receptor. Therefore, restoration of miR-29 expression in IPF lungs could not only inhibit the accumulation of ECM but also normalize the sensitivity to apoptosis in lung fibroblasts, which may be an effective strategy for treatment of IPF.
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Sun, Xiao-hui, Wen-jie Fan, Zong-jian An, and Yong Sun. "Inhibition of Long Noncoding RNA CRNDE Increases Chemosensitivity of Medulloblastoma Cells by Targeting miR-29c-3p." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 28, no. 1 (February 7, 2020): 95–102. http://dx.doi.org/10.3727/096504019x15742472027401.
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Long noncoding RNA CRNDE (CRNDE) recently emerged as a carcinogenic promoter in various cancers including medulloblastoma. However, the functions and molecular mechanisms of CRNDE to the acquired drug resistance of medulloblastoma are still unclear. The transcript levels of CRNDE were examined in four medulloblastoma cell lines exposed to cisplatin treatment, and IC50 values were calculated. Effects of CRNDE knockdown or miR-29c-3p overexpression on cell viability, colony formation, apoptosis, migration, and invasion were assessed using the CCK-8, colony formation assay, flow cytometry, and Transwell assays, respectively. RNA pulldown and RNA-binding protein immunoprecipitation (RIP) were performed to confirm the molecular interactions between CRNDE and miR-29c-3p involved in medulloblastoma cells. The in vivo role of CRNDE knockdown or miR-29c-3p overexpression on tumor growth and apoptosis was evaluated in a xenograft mouse model of human medulloblastoma. The transcript levels of lncRNA CRNDE were significantly higher in cisplatin-treated tumor cells with higher IC50 values. Depletion of CRNDE inhibited tumor cell proliferation and colony formation, induced cell apoptosis, and suppressed migration and invasion in medulloblastoma cells. Moreover, overexpression of miR-29c-3p inhibited tumor cell proliferation and colony formation, migration, and invasion, and enhanced apoptosis and chemosensitivity to cisplatin. In addition, CRNDE was found to act as a miR-29c-3p sponge. Furthermore, in vivo experiments showed the CRNDE/miR-29c-3p interactions involved in medulloblastoma. Our study demonstrates that CRNDE acts as a critical mediator of proliferation, apoptosis, migration, invasion, and resistance to chemotherapeutics via binding to and negatively regulating miR-29c-3p in medulloblastoma cells. These results provide novel molecular targets for treatment of medulloblastoma.
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Herawati, Cita. "CLINICAL SIGNIFICANCE OF PLASMA MIR-21, MIR-141, MIR-29C, AND MIR-BART7 IN PATIENTS WITH LOCALLY ADVANCED NASOPHARYNGEAL CANCER AND THEIR ALTERATIONS AFTER CHEMORADIATION THERAPY." INTERNATIONAL JOURNAL OF NASOPHARYNGEAL CARCINOMA (IJNPC) 1, no. 02 (September 17, 2019): 45–49. http://dx.doi.org/10.32734/ijnpc.v1i2.1136.
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Introduction:
Plasma microRNAs (miRNAs) are biological markers that have been extensively studied in cancer, including nasopharyngeal cancer (NPC). The clinical significance of miRNA in NPC patients in Indonesia has never been studied.
Objective:
This study was aimed to know the expression of plasma miRNAs in NPC patients (miR-21, miR-29c, miR-141dan miR-BART7) and their relationship with clinicopathological characteristics and treatment response.
Method:
This was a cohort, longitudinal study among locally advanced NPC patients (stage IIB-IVB) in Dharmais Cancer Hospital, Jakarta. miRNA expression was assayed using quantitative real-time polymerase chain reaction (qRT-PCR) technique. Four miRNAs were evaluated, i.e., miR-21, miR-29c, miR-141, and EBV-miR-BART7. The results were normalized against a reference gene, miR-16.
Result:
A total of 52 patients and 10 normal subjects were enrolled in this study; 17 of them completed treatment. Patients’ mean age was 45.1+12.53 (14-68) years. The ratio between men and women was 3:1. MiR-21 and miR-29c could be detected in all subjects; miR-141 was detected in 22 (42.3%) and EBV-miR-BART7 in 26 (50%) subjects. There was no significant difference between miR-21 or miR-29c expression between before and after therapy. However, miR-21 expressions tend to decrease in a patient with complete response (CR) (4.13+3.65 vs. 2.74+3.23; p=0.650) and tend to increase in patients with partial response (PR) (3.00+5.86 vs. 8.77+8.43; p=0.465). There was no difference of miR-29c expression between CR and PR patients.
Conclusion:
Our study shows that not all miRNA can be detected in the plasma of NPC patients. Levels of miRNA expressions in these locally advanced patients are similar. Expression of miR-21 is potentially used as a biomarker of evaluating treatment response in NPC patients.
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Wu, Liangqin, Songguo Li, Peng Shu, and Qian Liu. "Effect of miR-488 on Colon Cancer Biology and Clinical Applications." Evidence-Based Complementary and Alternative Medicine 2022 (May 5, 2022): 1–6. http://dx.doi.org/10.1155/2022/2138954.
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Objective. To explore the expression levels of miR-488, miR-29c-3p, and growth differentiation factor 15 (GDF15) in colon cancer tissue and analyze their relationship with clinicopathological features in patients with colon cancer. Methods. The study was conducted from November 2012 to November 2020. A total of 200 patients with colon cancer were treated in our hospital during this period. During the operation, the colon cancer tissues and the adjacent tissues whose distance from the cancer tissues were more than 5 cm were collected, and the expression levels of miR-488, miR-29c-3p, and GDF15 mRNA in colon cancer tissues were detected by qRT-PCR (real-time fluorescence quantitative). The relationship between them and the clinicopathological features and prognosis of patients with colon cancer were analyzed and discussed. Results. The level of miR-488 in colon cancer tissues was lower than that in adjacent tissues, but the levels of miR-29c-3p and GDF15 mRNA in colon cancer tissues were higher than those in adjacent tissues ( P < 0.05 ). Compared with paracancerous tissues, the expression rates of miR-29c-3p and GDF15 protein were higher in colon cancer tissues ( P < 0.05 ). There was no difference in age, sex, tumor location, and tumor diameter between high expression of miR-488 group and low expression of miR-488 group ( P > 0.05 ). The degree of differentiation, depth of invasion, TNM stage, lymph node metastasis, and other factors have a direct impact on the level of miR-488 and the expression of miR-29c-3p ( P < 0.05 ). The depth of invasion, TNM stage, and lymph node metastasis could affect the expression of GDF15 in patients with colon cancer ( P < 0.05 ). Conclusion. miR-488, miR-29c-3p, and GDF15 in colon cancer tissue are related to the clinicopathological features of patients in varying degrees and may become markers after early warning of colon cancer, which can provide effective guidance for clinical diagnosis and treatment.
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Williams, Allison Lesher, Chad B. Walton, Keith A. MacCannell, Abigail Avelar, and Ralph V. Shohet. "HIF-1 regulation of miR-29c impairs SERCA2 expression and cardiac contractility." American Journal of Physiology-Heart and Circulatory Physiology 316, no. 3 (March 1, 2019): H554—H565. http://dx.doi.org/10.1152/ajpheart.00617.2018.
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The principal regulator of cellular response to low oxygen is hypoxia-inducible factor (HIF)-1, which is stabilized in several forms of heart failure. Our laboratory developed a mouse strain in which a stable form of HIF-1 can be inducibly expressed in cardiomyocytes. Strikingly, these mice show a rapid decrease in cardiac contractility and a rapid loss of SERCA2 protein, which is also seen in heart failure. Interestingly, while the SERCA2 transcript decreased, it did not fully account for the observed decrease in protein. We therefore investigated whether HIF-1-regulated microRNA could impair SERCA translation. Multiple screening analyses identified the microRNA miR-29c to be substantially upregulated upon HIF-1 induction and to have complementarity to SERCA, and therefore be a potential regulator of SERCA2 expression in hypoxia. Subsequent evaluation confirmed that miR-29c reduced SERCA2 expression and Ca2+ reuptake. Additionally, administration of an antagonist sequence (antimir) improved cardiac contractility and SERCA2 expression in HIF transgenic mice. To extend the significance of these findings, we examined miR-29c expression in physiological hypoxia. Surprisingly, miR-29c decreased in these settings. We also treated mice with antimir before infarction to see if further suppression of miR-29c could improve cardiac function. While no improvement in contractility or SERCA2 was observed, reduction of heart size after infarction indicated that the antimir could modulate cardiac physiology. These results demonstrate that while a HIF-1-regulated microRNA, miR-29c, can reduce SERCA2 expression and contractility, additional factors in the ischemic milieu may limit these effects. Efforts to develop miRNA-based therapies will need to explore and account for these additional countervailing effects. NEW & NOTEWORTHY Our study demonstrated hypoxia-inducible factor-1-dependent upregulation of miR-29c, which, in turn, inhibited SERCA2 expression and reduced cardiac contractility in a transgenic overexpression system. Interestingly, these results were not recapitulated in a murine myocardial infarction model. These results underscore the complexity of the pathological environment and highlight the need for therapeutic target validation in physiologically relevant models. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/hif1-regulates-mir-29c-and-serca2/ .
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Xiao, Lan, Qiong Zhang, Xi Huang, Aihua He, Shi Xie, and Yanping Li. "Endometrial stromal cell miR-29c-3p regulates uterine contraction." Reproduction 158, no. 6 (December 2019): 493–501. http://dx.doi.org/10.1530/rep-19-0196.
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Uterine peristalsis plays a vital role in fertility and female reproductive health. Although uterine peristalsis is thought to be correlated with some hormones and uterine pathologies, the physiological mechanisms underlying uterine peristalsis remain not quite clear. This study aimed to identify changes in miRNA in the endometrium of patients with abnormally high-frequency (hyper-) and low-frequency (hypo-) peristalsis to clarify whether miRNAs regulate uterine peristalsis. We used a miRNA microarray and RT-qPCR to identify changes in miRNA in endometrial tissue, a collagen gel contraction assay on co-cultured human endometrial stromal cells (ESCs) to analyze how the altered regulation of miRNAs influences uterine smooth muscle (USM) contraction, Western blots and other assays to elucidate the potential mechanisms involved. We found that among several differentially regulated miRNAs, miR-29c-3p was overexpressed in endometrial samples from patients with hypoperistalsis; oxytocin receptor (OXTR) expression was low in endometrial samples from patients with hypoperistalsis. Bioinformatic analysis and luciferase assays indicated that OXTR is a target of miR-29c-3p, which attenuates its expression. Additionally, downregulation of miR-29c-3p in ESC cultures increased the expression of aldo-keto reductase family 1, member C3 (AKR1C3) and increased the release of prostaglandin F2 alpha (PGF2α). Co-cultured ESCs overexpressing miR-29c-3p reduced USM cell contractions; the opposite tendency was found when ESCs were transfected with a miR-29c-3p inhibitor. To conclude, miR-29c-3p in endometrial cells regulates uterine contractility by attenuating the expression of OXTR and reducing PGF2α release.
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Sun, Chen-Min, Wen-Yi Zhang, Shu-Yan Wang, Gang Qian, Dong-Liang Pei, and Guang-Ming Zhang. "Fer exacerbates renal fibrosis and can be targeted by miR-29c-3p." Open Medicine 16, no. 1 (January 1, 2021): 1378–85. http://dx.doi.org/10.1515/med-2021-0319.
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Abstract Aim Renal fibrosis (RF) is a common clinical condition leading to irreversible renal function loss. Tyrosine kinase proteins and microRNAs (miRs) are associated with pathogenesis and we aim to investigate the role of Fer and its partner miR(s) in RF. Method In silico reproduction of Mouse Kidney FibrOmics browser was performed to identify potential miR(s) and target gene(s). In vivo validation was performed in C57BL/6 mice with unilateral ureteral obstruction (UUO). In vitro validation was performed in rat kidney fibroblast NRK-49F cells. Mimics and inhibitors of miR-29c-3p were constructed. The target gene Fer was monitored by RT-PCR and western blotting. The levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α in serum and media were measured by ELISA. Results The Fer expression and protein level were gradually increased during 14 days of UUO modeling. miR-29c-3p expression was strongly correlated with that of Fer. In vivo validation showed increased expressions of fibrosis-associated genes and increased phospoho-Smad3 level in the UUO model. Fer-knockdown (KD) significantly decreased expressions of fibrosis-associated genes. Pharmaceutical inhibition of Fer showed similar effects to miR-29c-3p, and miR inhibition showed a significant decrease of excretion of inflammatory factors. Conclusion Dysregulation of miR-29c-3p and Fer plays a role in RF. Pharmaceutical or genetic inhibition of Fer may serve as the potential treatment for RF.
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Lu, Yebin, Ling Tang, Zhipeng Zhang, Shengyu Li, Shuai Liang, Liandong Ji, Bo Yang, Yu Liu, and Wei Wei. "Long Noncoding RNA TUG1/miR-29c Axis Affects Cell Proliferation, Invasion, and Migration in Human Pancreatic Cancer." Disease Markers 2018 (November 22, 2018): 1–10. http://dx.doi.org/10.1155/2018/6857042.
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Given the low resection rate and chemoresistance of patients with pancreatic cancer (PC), their survival rates are typically poor. Long noncoding RNAs (lncRNAs) have recently been shown to play an important role in tumourigenesis and human cancer progression, including in PC. In this study, we aimed to investigate the role of taurine-upregulated gene 1 (TUG1) in PC. A quantitative polymerase chain reaction was used to analyse TUG1 expression in PC tissues and peritumoural normal tissues. TUG1 was overexpressed in PC tissues compared with that in peritumoural normal tissues, and the high expression of TUG1 was associated with the poor prognosis of patients with PC. Furthermore, TUG1 knockdown significantly inhibited the proliferation and invasion of PC cells both in vitro and in vivo, while overexpression TUG1 promoted tumour cell proliferation, migration, and invasion. TUG1 directly targeted miR-29c, a tumour suppressor in several cancers. TUG1 knockdown significantly increased the expression of miR-29c and subsequently induced the downregulation of integrin subunit beta 1 (ITGB1), matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9). The downregulation of miR-29c abolished the TUG1 knockdown-mediated inhibition of tumour growth in vitro and in vivo, whereas the upregulation of miR-29c enhanced the effects of TUG1 knockdown on PC cells. In conclusion, we demonstrate for the first time the oncogenic role of TUG1 in PC. The downregulation of TUG1 significantly inhibited the growth and migratory ability of PC cells in vitro and in vivo by targeting miR-29c. Our study provides a novel potential diagnostic biomarker and therapeutic target for PC.
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Lv, Lin-Li, Yu-Han Cao, Hai-Feng Ni, Min Xu, Dan Liu, Hong Liu, Ping-Sheng Chen, and Bi-Cheng Liu. "MicroRNA-29c in urinary exosome/microvesicle as a biomarker of renal fibrosis." American Journal of Physiology-Renal Physiology 305, no. 8 (October 15, 2013): F1220—F1227. http://dx.doi.org/10.1152/ajprenal.00148.2013.
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Micro (mi)RNAs are frequently dysregulated in the development of renal fibrosis. Exosomes are small membrane vesicles that could be isolated from urine secreted from all nephron segments. Here we sought to observe for the first time whether miRNA in urine exosome could serve as a potential biomarker of renal fibrosis. Urine samples were collected from 32 chronic kidney disease (CKD) patients who underwent kidney biopsy and 7 controls. Exosome was isolated and confirmed by immunogold staining of exosome marker. Members of miR-29, miR-200, and RNU6B as endogenous control were detected by RT quantitative PCR. Electronic microscopy verified a typical shape of exosome with average size of 65.1 nm and labeled it with anti-CD9 and anti-aquaporin 2 antibody. Members of miR-29 and miR-200 are readily measured with reduced levels compared with controls ( P < 0.05) and can robustly distinguish CKD from controls [area under the curve (AUC) varied from 0.902 to 1 by receiver operating characteristics analysis]. miR-29c correlated with both estimated glomerular filtration rate ( r = 0.362; P < 0.05) and degree of tubulointerstitial fibrosis ( r = −0.359; P < 0.05) for CKD patients. Moreover, miRNA in exosome was decreased in mild fibrosis group compared with moderated to severe group. miR-29a and miR-29c could predict degree of tubulointerstitial fibrosis with AUC of 0.883 and 0.738 ( P < 0.05). The sensitivity and specificity for distinguishing mild from moderate to severe fibrosis were 93.8 and 81.3% with the use of miR-29a and 68.8 and 81.3% for miR-29c. Overall, miR-29c in urinary exosome correlates with both renal function and degree of histological fibrosis, suggesting it as a novel, noninvasive marker for renal fibrosis.
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Khorram, O., T. D. Chuang, and W. J. Pearce. "Long-term effects of maternal undernutrition on offspring carotid artery remodeling: role of miR-29c." Journal of Developmental Origins of Health and Disease 6, no. 4 (May 26, 2015): 342–49. http://dx.doi.org/10.1017/s2040174415001208.
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The purpose of this study was to examine the hypothesis that excess maternal glucocorticoids in response to maternal undernutrition programs the expression of extracellular matrix (ECM) components potentially by miR-29c. We measured the expression of mRNA (qRT-PCR) and protein (Western blot) for collagen 3A1, collagen 4A5 and matrix metalloproteinase 2 (MMP2) in offspring carotid arteries from three groups of dams: 50% food-restricted in latter half of gestation [maternal undernutrition (MUN)], MUN dams who received metyrapone (MET) (500 mg/ml ) in drinking water from day 10 of gestation to term, and control dams fed an ad libitum diet. The expression of miR-29c was significantly decreased at 3 weeks, 3 months and 9 months in MUN carotid arteries, and these decreases in expression were partially blocked by treatment of dams with MET. The expression pattern of ECM genes that are targets of miR-29c correlated with miR-29c expression. Expression of mRNA was increased for elastin (ELN) and MMP2 mRNA in 3-week MUN carotids; in 9-month carotids there were also significant increases in expression of Col3A1 and Col4A5. These changes in mRNA expression of ECM genes at 3 weeks and 9 months were blocked by MET treatment. Similarly, the expression of ELN and MMP2 proteins at 3 weeks were increased in MUN carotids, and by 9 months there were also increases in expression of Col3A1 and Col4A5, which were blocked by MET in MUN carotids. Overall, the results demonstrate a close correlation between expression of miR-29c and the ECM proteins that are its targets thus supporting our central hypothesis.
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Arechaga-Ocampo, Elena, Cesar Lopez-Camarillo, Nicolas Villegas-Sepulveda, Claudia H. Gonzalez-De la Rosa, Isidro X. Perez-Añorve, Reynalda Roldan-Perez, Ali Flores-Perez, et al. "Tumor suppressor miR-29c regulates radioresistance in lung cancer cells." Tumor Biology 39, no. 3 (March 2017): 101042831769501. http://dx.doi.org/10.1177/1010428317695010.
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Radiotherapy is an important treatment option for non-small cell lung carcinoma patients. Despite the appropriate use of radiotherapy, radioresistance is a biological behavior of cancer cells that limits the efficacy of this treatment. Deregulation of microRNAs contributes to the molecular mechanism underlying resistance to radiotherapy in cancer cells. Although the functional roles of microRNAs have been well described in lung cancer, their functional roles in radioresistance are largely unclear. In this study, we established a non-small cell lung carcinoma Calu-1 radioresistant cell line by continuous exposure to therapeutic doses of ionizing radiation as a model to investigate radioresistance-associated microRNAs. Our data show that 50 microRNAs were differentially expressed in Calu-1 radioresistant cells (16 upregulated and 34 downregulated); furthermore, well-known and novel microRNAs associated with resistance to radiotherapy were identified. Gene ontology and enrichment analysis indicated that modulated microRNAs might regulate signal transduction, cell survival, and apoptosis. Accordingly, Calu-1 radioresistant cells were refractory to radiation by increasing cell survival and reducing the apoptotic response. Among deregulated microRNAs, miR-29c was significantly suppressed. Reestablishment of miR-29c expression in Calu-1 radioresistant cells overcomes the radioresistance through the activation of apoptosis and downregulation of Bcl-2 and Mcl-1 target genes. Analysis of The Cancer Genome Atlas revealed that miR-29c is also suppressed in tumor samples of non-small cell lung carcinoma patients. Notably, we found that low miR-29c levels correlated with shorter relapse-free survival of non-small cell lung carcinoma patients treated with radiotherapy. Together, these results indicate a new role of miR-29c in radioresistance, highlighting their potential as a novel biomarker for outcomes of radiotherapy in lung cancer.
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Du, Xing, Lu Liu, Wangjun Wu, Pinghua Li, Zengxiang Pan, Lifan Zhang, Jiying Liu, and Qifa Li. "SMARCA2 is regulated by NORFA–miR-29c, a novel pathway that controls granulosa cell apoptosis and is related to female fertility." Journal of Cell Science 133, no. 23 (November 4, 2020): jcs249961. http://dx.doi.org/10.1242/jcs.249961.
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ABSTRACTSMARCA2, an evolutionarily conserved catalytic ATPase subunit of SWI/SNF complexes, has been implicated in development and diseases; however, its role in mammalian ovarian function and female fertility is unknown. Here, we identified and characterized the 3′-UTR of the porcine SMARCA2 gene and identified a novel adenylate number variation. Notably, this mutation was significantly associated with sow litter size traits and SMARCA2 levels, due to its influence on the stability of SMARCA2 mRNA in ovarian granulosa cells (GCs). Immunohistochemistry and functional analysis showed that SMARCA2 is involved in the regulation of follicular atresia by inhibiting GC apoptosis. In addition, miR-29c, a pro-apoptotic factor, was identified as a functional miRNA that targets SMARCA2 in GCs and mediates regulation of SMARCA2 expression via the NORFA–SMAD4 axis. Although a potential miR-29c-responsive element was identified within NORFA, negative regulation of miR-29c expression by NORFA was not due to activity as a competing endogenous RNA. In conclusion, our findings demonstrate that SMARCA2 is a candidate gene for sow litter size traits, because it regulates follicular atresia and GC apoptosis. Additionally, we have defined a novel candidate pathway for sow fertility, the NORFA–TGFBR2–SMAD4–miR-29c–SMARCA2 pathway.This article has an associated First Person interview with the first author of the paper.
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Zong, Yuanyuan, Hailin Wang, Wei Dong, XiongZhi Quan, Hua Zhu, YanFeng Xu, Lan Huang, Chunmei Ma, and Chuan Qin. "miR-29c regulates BACE1 protein expression." Brain Research 1395 (June 2011): 108–15. http://dx.doi.org/10.1016/j.brainres.2011.04.035.
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Chaves, Juliana Ramos, Carolina Rosal Teixeira de Souza, Antonio André Conde Modesto, Fabiano Cordeiro Moreira, Eliel Barbosa Teixeira, Jonathan Souza Sarraf, Thaís Suellen Ramos Allen, Taíssa Maíra Thomaz Araújo, Andre Salim Khayat, and Luis Eduardo Werneck De Carvalho. "Effects of alkaline water intake on gastritis and miRNA expression (miR-7, miR-155, miR-135b and miR-29c) in the Amazon population." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16544-e16544. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16544.
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e16544 Background: It is known that abnormal expression of miRNAs in the gastric cancer (GC) contributes to its carcinogenesis. Therefore, ingestion of commercial (usual) water on a daily basis may be a contributing factor for the occurrence of alterations in the gastric mucosal. In this study, it was evaluated the expression of the miRNAs miR-29c, miR-7, miR-155, and miR-135b in the gastric tissue of patients with gastritis before and after the consumption of alkaline water (pH range from 8.0 to 10.0), as well as the clinic pathological characteristics. Methods: 50 subjects from the Amazon region, diagnosed with gastritis that routinely used commercial (usual) water with a pH lower than 5.0, were enrolled to change the consume water to a pH of 8.5 to 10.0 for 5 months. Results: Endoscopic findings of gastritis were such different (less severe disease), p = 0.024; in 43% diagnosed with moderate gastritis upfront esophagogastroduodenoscopy (EGD) presented mild gastritis after the consumption of alkaline water, according to study methods; there were no worsening gastritis and there were a significant increase in the expression of miR-135b (p = 0.039) and miR-29c (p = 0.039). Conclusions: Modified pH range water (from 8.0 to 10.0) ingested for 5 months was able lead to a less severe gastritis according to the Sidney classification system, suggesting that this lifestyle change represented a clinical benefit in patients with gastritis on the Amazon region. In addition, higher expression of miR-135b and miR-29c was observed after the consumption of alkaline water for 5 months. [Table: see text]
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Oto, Julia, Emma Plana, Álvaro Fernández-Pardo, Fernando Cana, Manuel Martínez-Sarmiento, César D. Vera-Donoso, Francisco España, and Pilar Medina. "Identification of miR-29c-3p as a Robust Normalizer for Urine microRNA Studies in Bladder Cancer." Biomedicines 8, no. 11 (October 22, 2020): 447. http://dx.doi.org/10.3390/biomedicines8110447.
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Bladder cancer (BC) is among the most frequent malignancies worldwide, being the most expensive cancer to treat and monitor and the most lethal urological cancer. Urine microRNAs (miRNAs) have been proposed as novel non-invasive biomarkers to early diagnose and monitor BC patients in order to avoid the performance of current aggressive diagnostic techniques. However, huge discrepancies arise among studies mainly due to the lack of standardization in the normalization, a crucial step in all miRNA studies. Our aim was to identify the best miRNA normalizer for miRNA studies in urine of BC patients. We evaluated the performance of 110 candidate miRNAs in urine of 35 BC patients and 15 healthy controls by Real Time quantitative Polymerase Chain Reaction (RT-qPCR) followed by a stability analysis with RefFinder. In this screening stage, miR-29c-3p arose as the most stably expressed miRNA in BC and controls, with a good expression level. Stability of miR-29c-3p expression was validated in an independent cohort of 153 BC patients and 57 controls. Finally, we evaluated the robustness of miR-29c-3p as normalizer in the expression study of miR-200c-3p, a potential diagnostic marker for BC. We propose miR-29c-3p as a normalizer for miRNA studies in BC urine. This is the first study that characterizes a reliable normalizer that may allow the comparison of future urine miRNA studies as non-invasive biomarkers for BC diagnosis and monitoring.
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Wang, Yanjing, and Yuanyuan Li. "MiR-29c inhibits HCV replicationviaactivation of type I IFN response by targeting STAT3 in JFH-1-infected Huh7 cells." RSC Advances 8, no. 15 (2018): 8164–72. http://dx.doi.org/10.1039/c7ra12815k.
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Alves, Paula Ketilly Nascimento, André Cruz, William J. Silva, Siegfried Labeit, and Anselmo Sigari Moriscot. "miR-29c Increases Protein Synthesis in Skeletal Muscle Independently of AKT/mTOR." International Journal of Molecular Sciences 23, no. 13 (June 28, 2022): 7198. http://dx.doi.org/10.3390/ijms23137198.
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microRNAs negatively regulate gene expression by blocking translation or increasing mRNA degradation. In skeletal muscle, these molecules play important roles in adaptive responses, and ongoing investigations are necessary to understand the fine-tune regulation of skeletal muscle mass. Herein we showed that skeletal muscle overexpression of miR-29c increased fiber size and force at 7 and 30 days after electrotransfer. At both time points, AKT/mTOR pathway components were downregulated, and, surprisingly, overall protein synthesis was strongly elevated at day 7, which normalized by day 30 after pCMVmiR-29c electrotransfer. These results indicate that miR-29c expression induces skeletal muscle hypertrophy and gain of function, which involves increased overall protein synthesis in spite of the deactivation of the AKT/mTOR pathway.
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Catapano, Francesco, Dominic Scaglioni, Kate Maresh, Pierpaolo Ala, Joana Domingos, Victoria Selby, Valeria Ricotti, et al. "Novel free-circulating and extracellular vesicle-derived miRNAs dysregulated in Duchenne muscular dystrophy." Epigenomics 12, no. 21 (November 2020): 1899–915. http://dx.doi.org/10.2217/epi-2020-0052.
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Aim: To perform cross-sectional and longitudinal miRNA profiling in plasma from Duchenne muscular dystrophy (DMD) subjects and find non-invasive biomarkers in DMD. Subjects/materials & methods: Plasma was collected from 14 age and sex matched controls and 46 DMD subjects. Free-circulating and extracellular vesicle (EV)-derived miRNA expression was measured by RT-qPCR. Results: Free-circulating and EVs derived miR-29c-3p and miR-133a-3p are dysregulated in DMD subjects. Free-circulating and EV-derived miR-29c-3p are reduced in DMD subjects undergoing daily corticosteroid treatment. Free-circulating miR-1-3p and miR-122-5p are longitudinally upregulated in ambulant DMD subjects. Conclusion: We detected novel free-circulating and EV-derived dysregulated miRNAs in plasma from DMD subjects and characterized the longitudinal profile of free-circulating miRNA on plasma from DMD subjects.
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Nuckel, Holger, Crista Ochsenfarth, Ludger Sellmann, Jan Duerig, Ulrich Duehrsen, and Ulrich Frey. "A New MicroRNA Risk Model for Prediction of Clinical Outcome In Chronic Lymphocytic Leukemia." Blood 116, no. 21 (November 19, 2010): 3592. http://dx.doi.org/10.1182/blood.v116.21.3592.3592.
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Abstract Abstract 3592 Introduction: Increasing experimental evidence supports the idea of aberrant microRNA (miRNA) expression in cancer pathogenesis, especially in chronic lymphocytic leukemia (CLL). Recently, aberrant expression of miR-29c and miR-223 has been associated with CLL outcome. Moreover, low expression of miR-34a in CLL is associated with p53 inactivation and also chemotherapy-refractory disease. Therefore, we investigated miR-29c, miR-223 and miR-34a expression in a large representative cohort of 110 CLL patients in order to assess the role of these miRNAs in risk prediction in B-CLL. Methods: Mononuclear cells of B-CLL were isolated from whole blood by centrifugation on a Ficoll/Hypaque gradient and cryopreserved in liquid nitrogen. MicroRNA was extracted from native liquid-nitrogen frozen cells using the QIAGEN miRNeasy® mini kit (Qiagen, Hilden, Germany). The relative expression of mature miRNAs was quantified using the TaqMan MicroRNA RT kit and TaqMan® MicroRNA Assays (Applied Biosystems, Foster City, California) on the ABI 7500 Real Time PCR System (Applied Biosystems, Foster City, California). RNU6B was used as internal control. The relative expression of each microRNA of interest to RNU6B was calculated using the formula miRNA of interest/RNU6B=2-deltaCt(miRNA-RNU6B). Result: The impact of the three miRNA expressions on treatment-free survival (TFS) and overall survival (OS) was assessed by performing “Receiver Operating Characteristics” (ROC) curve analysis. Patients with low miR-29c, miR-223 or miR-34a expression had a shorter TFS and OS than those patients with high expression: miR-29c: TFS 49 vs 91 months (p=0.081); OS 164 months vs not reached (p=0.093) miR-223: TFS 27 vs 84 months (p=0.035); OS 132 months vs not reached (p=0.001) miR-34a: TFS 46 vs 83 months (p=0.084); OS 132 months vs not reached (p=0.001) Furthermore, we investigated whether combining information on the expression of miRNAs could help refine the prognostic information provided by either of the three risk factors (RF) alone. Adding the number of risk factors this approach allowed for highly significant separation of our patient cohort into four subgroups, which differed significantly with regard to their clinical outcome. TFS: 0 RF 99 months; 1 RF 75 months; 2 RF 26 months; 3 RF 22 months (p=0.008) OS: 0 RF not reached; 1 RF not reached; 2 RF 164 months; 3 RF 132 months (p<0.0001) Moreover, in multivariate analysis the miRNA risk model was a significant independent prognostic factor (HR 1.3; 95%CI 1.0–1.8; p=0.04) next to the stage of Binet (HR 2.1; 95%CI 1.4–3.4; p=0.001) and ZAP-70 status (HR 3.0; 95%CI 1.5–5.9; p=0.002). Conclusion: Combined analysis of miR-29c, miR-223 and miR-34a expression in a risk model may help optimize currently available prognostic instruments. Future studies are warranted to elucidate the role of miRNAs as a prognostic factor for response and clinical outcome. Disclosures: No relevant conflicts of interest to declare.
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Zhao, Kai, Yaoping Chen, Ruifeng Yang, Yang Bai, Cuiling Li, Honggang Li, and Chengliang Xiong. "miR-424/322 is downregulated in the semen of patients with severe DNA damage and may regulate sperm DNA damage." Reproduction, Fertility and Development 28, no. 10 (2016): 1598. http://dx.doi.org/10.1071/rd15052.
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Sperm DNA integrity is an essential factor for accurate transmission of genetic information. Human sperm DNA damage is a common cause of male infertility but the exact mechanism remains poorly understood. Considering the vital role of microRNA (miRNA) in multiple pathophysiological processes, we hypothesised that testicular miRNA is involved in sperm DNA damage during spermatogenesis. Infertile patients with high sperm DNA fragment index (DFI; n = 94) were selected from 1090 infertile men and a total of 18 testis-specific seminal miRNAs previously identified from human seminal plasma were chosen and tested. miR-29c and miR-424 were downregulated in men with high DFI. The inhibition of these two miRNAs in mice confirmed the role of miR-424 (murine homologue miR-322) in sperm DNA damage during spermatogenesis; by contrast, miR-29c exhibited a negative result. Thus, miR-424/322 is involved in sperm DNA damage. Furthermore, the dysregulation of this miRNA can induce DNA double-strand breaks during spermatogenesis.
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Lochmanova, Jana, Marek Mraz, Veronika Navrkalova, Barbora Dvorakova, Boris Tichy, Karla Plevova, Ludmila Sebejova, et al. "Mutational Analysis of Mir-29 Family Members in Chronic Lymphocytic Leukemia." Blood 118, no. 21 (November 18, 2011): 1770. http://dx.doi.org/10.1182/blood.v118.21.1770.1770.
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Abstract Abstract 1770 Background: MicroRNAs (miRNAs) are small non-coding RNA molecules regulating gene expression by inhibition of mRNA translation and/or stability. Numerous miRNAs were described as tumor suppressor genes or oncogenes. In this respect, miR-29 family belongs to the most important miRNAs involved in CLL biology. Three different isoforms of the miR-29 (miR-29a-2, miR-29b-2 and miR-29c) were shown to be down-regulated in aggressive CLL (Calin et al., 2004; Mraz et al., 2009). Moreover, miR-29 was suggested to target the expression of MCL1, CDK6 and TCL1, a critical oncogene in aggressive CLL. Recently, the generation of transgenic mice over-expressing miR-29 in B-cells demonstrated its direct role in CLL pathogenesis. Additionally, mutations in miR-29c and miR-29b-2 have been also detected in CLL patients (Calin et al., 2005); however, their impact and frequency have yet to be elucidated. Aims: In this study, we searched for novel sequence variations in three members of the miR-29 family (miR-29a, miR-29b-2 and miR-29c) using re-sequencing microarray and Sanger sequencing. Methods: The pre-miRNAs (29a, 29b-2, 29c) and 107 other pre-miRNAs were analyzed by a custom re-sequencing microarray (Affymetrix, 50K) in 98 high-risk CLL patients (81.6% of patients had unmutated IgVH; 37.8% had a mutation in the TP53 gene). To cover the whole genomic area of pre-miRNAs, ∼20 nucleotides from both 5' and 3' ends of pri-miRNAs were also analysed. MiRNAs were amplified from genomic DNA isolated from peripheral blood cells (CLL lymphocytes or mononuclear cells) using long range PCR. Amplicons were pooled, fragmented and co-hybridized on the array according to the manufacturer's protocol. Sanger sequencing was used to confirm the presence of the mutations detected by microarray. The genomic regions (455-bp, 940-bp) of pri-miR-29c and pri-miR-29b-2, respectively, were further analyzed by Sanger sequencing in another 192 CLL patients (63.5% with unmutated IgVH; 21.4% with TP53 gene mutation). Results: Using resequencing microarray and confirmatory Sanger sequencing, one heterozygous variation (A/G +22 in 3') was found in the pri-miR-29a in one of 98 CLL patients. Screening of pri-miR-29c (455-bp genomic area) detected two substitutions in 4 of 192 CLL patients. In particular, the known G/A substitution (-31 in 5') was found as heterozygous in two patients. Additionally, novel heterozygous T/A substitution (+137 in 3') was found in two other patients. Screening of 940-bp genomic region of the pri-miR-29b-2 detected insertion (+A) (+107 in 3') in 22 of 192 patients. However, the known G/A substitution (+212 in 3') was not detected in our cohort. Furthermore, 2 novel heterozygous variations in pri-miR-29b-2 (C/G −169 in 5' and A/G − 256 in 5') were found in 5 and 2 patients, respectively. According to our results, pri-miR-29b-2 seems to be the most frequently mutated member of the miR-29 family, since three types of variations were detected in 29 of 192 CLL patients (15.1%). Two substitutions were found in pri-miR-29c in 4 of 192 CLL patients (2.1%) and only one substitution was detected in pri-miR-29a in one of 98 CLL patients (1%). Conclusion: We herein confirm that both known mutations and novel sequence variations are present in three members of the miR-29 family which is already implicated in CLL pathogenesis or progression. Altogether, we have found 6 types of variations in 34 of 290 analyzed CLL patients (11.7%). The insertion (+A) (+107 in 3') in pri-miR-29b-2 was the most common variation detected in our cohort of CLL patients; however, its impact on CLL pathogenesis has to be elucidated. Supported by the grants IGA-MZ-CR NT11218-6/2010, NS10439-3/2009, NS9858-3/2009, MPO-CR-FR-TI2/254 and MSMT-CR-MSM0021622430. Disclosures: Mayer: Roche: Consultancy, Honoraria, Institutional/personal grants and travel/accommodation expenses, Speakers Bureau; Astellas: Consultancy, Honoraria, Institutional/personal grants and travel/accommodation expenses, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Institutional/personal grants and travel/accommodation expenses, Speakers Bureau; Novartis: Consultancy, Honoraria, Institutional/personal grants and travel/accommodation expenses, Speakers Bureau; Fresenius Medical Care: Consultancy, Honoraria, Institutional/personal grants and travel/accommodation expenses, Speakers Bureau; Pfizer: Consultancy, Honoraria, Institutional/personal grants and travel/accommodation expenses, Speakers Bureau; Genzyme: Consultancy, Honoraria, Institutional/personal grants and travel/accommodation expenses, Speakers Bureau; GSK: Honoraria, Institutional/personal grants and travel/accommodation expenses, Speakers Bureau; Amgen:.
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Bozzini, Sara, Giovanni Zanframundo, Cecilia Bagnera, Eleonora Bozza, Sara Lettieri, Valentina Vertui, Veronica Codullo, et al. "A Proof-of-Concept Analysis of Plasma-Derived Exosomal microRNAs in Interstitial Pulmonary Fibrosis Secondary to Antisynthetase Syndrome." International Journal of Molecular Sciences 23, no. 23 (November 23, 2022): 14579. http://dx.doi.org/10.3390/ijms232314579.
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Antisynthetase syndrome (ASSD) is an autoimmune disease characterized by the positivity of autoantibodies against different aminoacyl transfer RNA (tRNA) synthetases. Morbidity and mortality of this disease are highly affected by interstitial lung disease (ILD) which is present in about 80% of patients. In this study, we investigated possible differences in 84 immune-related circulating miRNAs between ASSD patients with and without ILD; we enrolled 15 ASSD patients, 11 with ILD (ILD+) and 4 without ILD (ILD-), and 5 patients with idiopathic pulmonary fibrosis (IPF) as an additional control group. All patients were at disease onset and not on therapy at the time of inclusion. Differentially expressed miRNAs were identified in plasma-derived exosomes, using an miRNA PCR array (MIHS-111ZG, Qiagen, Hilden, Germany); miR-30a-5p and miR-29c-3p were upregulated in ASSD-ILD patients compared to patients without lung involvement (adjusted p-value < 0.05). IPF patients showed higher miR-29c-3p expression levels with respect to both ASSD and ASSD-ILD (p = 0.0005), whereas levels of miR-30a-5p were not different. miR-29c-3p and miR-30a-5p are overexpressed in ASSD-ILD+ patients compared with ILD−. These miRNAs are involved in the regulation of inflammation and fibrosis through their action on NF-κB and TGF-β1. Although the mechanistic role of these miRNAs in ASSD-ILD development has to be elucidated, we suggest that their exosome levels could be useful in identifying patients at risk of ILD.
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Visone, Rosa, Laura Z. Rassenti, Angelo Veronese, Cristian Taccioli, Stefan Costinean, Baltazar D. Aguda, Stefano Volinia, et al. "Karyotype-specific microRNA signature in chronic lymphocytic leukemia." Blood 114, no. 18 (October 29, 2009): 3872–79. http://dx.doi.org/10.1182/blood-2009-06-229211.
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Abstract Chromosomal abnormalities, immunoglobulin heavy chain variable–region (IGHV) gene mutation status, and ζ-associated protein 70 (ZAP-70) expression levels have independent prognostic relevance in chronic lymphocytic leukemia (CLL); however, their concordance is variable. Because deregulation of microRNAs has been linked to disease initiation and progression in CLL, we studied the value of the microRNAs as a signature for CLL patients with specific chromosomal abnormalities. We identified 32 microRNAs able to discriminate the 11q deletion, 17p deletion, trisomy 12, 13q deletion, and normal karyotype cytogenetic subgroups. The expression values of 9 among the 32 microRNAs (miR-151-3p, miR-34a, miR-29c, miR-29b, miR-155, miR-148a, miR-146a, miR-146b5p, and miR-640) were correlated with gene expression data from the same samples to assess their biologic impact on CLL. In this study we also found that IGHV unmutated, high expression of ZAP-70 protein, and low expression of the miR-223, miR-29c, miR-29b, and miR-181 family were strongly associated with disease progression in CLL cases harboring 17p deletion, whereas in those harboring trisomy 12 only high expression of the miR-181a, among the analyzed parameters, suggested more aggressive disease. Thus, the use of the microRNA-based classifications may yield clinically useful biomarkers of tumor behavior in CLL.
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Foiani, Greta, Gabriella Guelfi, and Maria Teresa Mandara. "MicroRNA Dysregulation in Canine Meningioma: RT-qPCR Analysis of Formalin-Fixed Paraffin-Embedded Samples." Journal of Neuropathology & Experimental Neurology 80, no. 8 (July 17, 2021): 769–75. http://dx.doi.org/10.1093/jnen/nlab057.
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Abstract MicroRNAs (miRNAs) are small non-coding RNAs that play key roles in tumorigenesis as modulators of cell signaling pathways. miRNA expression has been found to be dysregulated in several human and canine tumors, but data are not yet available on canine meningioma. In this study, we analyzed the expression of 12 miRNAs (i.e. miR-335, miR-200a, miR-98, miR-96, miR-190a, miR-29c, miR-219-5p, miR-155, miR-146a, miR-145, miR-136, miR-451) by RT-qPCR in a series of 41 formalin-fixed, paraffin-embedded canine meningiomas, and normal arachnoid samples. We identified 8 dysregulated miRNAs that might be involved in canine meningioma pathogenesis. Five miRNAs (i.e. miR-96, miR-145, miR-335, miR-200a, miR-29c), were downregulated in tumor samples and 3 (i.e. miR-136, miR-155, miR-146a) were upregulated. Moreover, miR-200a was overexpressed in grade III compared to grade I and grade II meningiomas, suggesting that it might have a dual role in tumor initiation and progression. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses suggest that dysregulated miRNAs might influence cellular processes and pathways mainly involved in tumor cell migration, extracellular matrix interactions, cell proliferation, and inflammatory responses. The characterization of miRNA functions in canine meningiomas is needed to assess their potential clinical utility, also in view of the relevance of the dog as a potential spontaneous animal model of human disease.
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Choi, Jason L., Patricia F. Kao, Elena Itriago, Yougen Zhan, James A. Kozubek, Andrew G. Hoss, Meredith G. Banigan, et al. "miR-149 and miR-29c as candidates for bipolar disorder biomarkers." American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 174, no. 3 (February 12, 2017): 315–23. http://dx.doi.org/10.1002/ajmg.b.32518.
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Hillen, Maarten R., Eleni Chouri, Maojie Wang, Sofie L. M. Blokland, Sarita A. Y. Hartgring, Arno N. Concepcion, Aike A. Kruize, et al. "Dysregulated miRNome of plasmacytoid dendritic cells from patients with Sjögren’s syndrome is associated with processes at the centre of their function." Rheumatology 58, no. 12 (May 25, 2019): 2305–14. http://dx.doi.org/10.1093/rheumatology/kez195.
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Abstract Objective A considerable body of evidence supports a role for type-I IFN in the pathogenesis of primary SS (pSS). As plasmacytoid dendritic cells (pDCs) are a major source of type-I IFN, we investigated their molecular regulation by measuring expression of a large set of miRNAs. Methods pDCs were isolated from peripheral blood of pSS patients (n = 30) and healthy controls (n = 16) divided into two independent cohorts (discovery and replication). Screening of 758 miRNAs was assessed by an OpenArray quantitative PCR-based technique; replication of a set of identified miRNAs was performed by custom array. Functional annotation of miRNA targets was performed using pathway enrichment. Novel targets of miR-29a and miR-29c were identified using a proteomic approach (stable isotope labelling with amino acids in cell culture). Results In the discovery cohort, 20 miRNAs were differentially expressed in pSS pDCs compared with healthy control pDCs. Of these, differential expression of 10 miRNAs was confirmed in the replication cohort. The dysregulated miRNAs were involved in phosphoinositide 3-kinase-Ak strain transforming and mammalian target of rapamycin signalling, as well as regulation of cell death. In addition, a set of novel protein targets of miR-29a and miR-29c were identified, including five targets that were regulated by both miRs. Conclusion The dysregulated miRNome in pDCs of patients with pSS is associated with aberrant regulation of processes at the centre of pDC function, including type-I IFN production and cell death. As miR-29a and miR-29c are pro-apoptotic factors and several of the novel targets identified here are regulators of apoptosis, their downregulation in patients with pSS is associated with enhanced pDC survival.
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Wang, Ying, Yanyan Li, Jing Sun, Qian Wang, Cuiyun Sun, Yaping Yan, Lin Yu, et al. "Tumor-suppressive effects of miR-29c on gliomas." NeuroReport 24, no. 12 (August 2013): 637–45. http://dx.doi.org/10.1097/wnr.0b013e3283630126.
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Darnet, Sylvain, Fabiano C. Moreira, Igor G. Hamoy, Rommel Burbano, André Khayat, Aline Cruz, Leandro Magalhães, et al. "High-Throughput Sequencing of miRNAs Reveals a Tissue Signature in Gastric Cancer and Suggests Novel Potential Biomarkers." Bioinformatics and Biology Insights 9s1 (January 2015): BBI.S23773. http://dx.doi.org/10.4137/bbi.s23773.
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Gastric cancer has a high incidence and mortality rate worldwide; however, the use of biomarkers for its clinical diagnosis remains limited. The microRNAs (miRNAs) are biomarkers with the potential to identify the risk and prognosis as well as therapeutic targets. We performed the ultradeep miRnomes sequencing of gastric adenocarcinoma and gastric antrum without tumor samples. We observed that a small set of those samples were responsible for approximately 80% of the total miRNAs expression, which might represent a miRNA tissue signature. Additionally, we identified seven miRNAs exhibiting significant differences, and, of these, hsa-miR-135b and hsa-miR-29c were able to discriminate antrum without tumor from gastric cancer regardless of the histological type. These findings were validated by quantitative real-time polymerase chain reaction. The results revealed that hsa-miR-135b and hsa-miR-29c are potential gastric adenocarcinoma occurrence biomarkers with the ability to identify individuals at a higher risk of developing this cancer, and could even be used as therapeutic targets to allow individualized clinical management.
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Vissers, Tessa A. C. M., Leonie Piek, Susana I. S. Patuleia, Aafke J. Duinmeijer, Marije F. Bakker, Elsken van der Wall, Paul J. van Diest, Carla H. van Gils, and Cathy B. Moelans. "Elevated miR-29c-5p Expression in Nipple Aspirate Fluid Is Associated with Extremely High Mammographic Breast Density." Cancers 14, no. 15 (August 5, 2022): 3805. http://dx.doi.org/10.3390/cancers14153805.
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High mammographic density (MD) is associated with an increased risk of breast cancer, however the underlying mechanisms are largely unknown. This research aimed to identify microRNAs (miRNAs) that play a role in the development of extremely dense breast tissue. In the discovery phase, 754 human mature miRNAs were profiled in 21 extremely high MD- and 20 very low MD-derived nipple aspirate fluid (NAF) samples from healthy women. In the validation phase, candidate miRNAs were assessed in a cohort of 89 extremely high MD and 81 very low MD NAF samples from healthy women. Independent predictors of either extremely high MD or miRNA expression were identified by logistic regression and linear regression analysis, respectively. mRNA targets and pathways were identified through miRTarBase, TargetScan, and PANTHER pathway analysis. Statistical analysis identified four differentially expressed miRNAs during the discovery phase. During the validation, linear regression (p = 0.029; fold change = 2.10) and logistic regression (p = 0.048; odds ratio = 1.38) showed that hsa-miR-29c-5p was upregulated in extremely high MD-derived NAF. Identified candidate mRNA targets of hsa-miR-29c-5p are CFLAR, DNMT3A, and PTEN. Further validation and exploration of targets and downstream pathways of has-miR-29c-5p will provide better insight into the processes involved in the development of high MD and in the associated increased risk of breast cancer.
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Qu, Yan, Haibing Xiao, Wen Xiao, Zhiyong Xiong, Wenjun Hu, Yaoying Gao, Zeyuan Ru, et al. "Upregulation of MIAT Regulates LOXL2 Expression by Competitively Binding MiR-29c in Clear Cell Renal Cell Carcinoma." Cellular Physiology and Biochemistry 48, no. 3 (2018): 1075–87. http://dx.doi.org/10.1159/000491974.
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Background/Aims: MIAT is a long noncoding RNA (lncRNA) involved in cell proliferation and the development of tumor. However, the exact effects and molecular mechanisms of MIAT in clear cell renal cell carcinoma (ccRCC) progression are still unknown. Methods: We screened the lncRNAs’ profile of ccRCC in The Cancer Genome Atlas database, and then examined the expression levels of lncRNA MIAT in 45 paired ccRCC tissue specimens and in cell lines by q-RT-PCR. MTS, colony formation, EdU, and Transwell assays were performed to examine the effect of MIAT on proliferation and metastasis of ccRCC. Western blot and luciferase assays were performed to determine whether MIAT can regulate Loxl2 expression by competitively binding miR-29c in ccRCC. Results: MIAT was up-regulated in ccRCC tissues and cell lines. High MIAT expression correlated with worse clinicopathological features and shorter survival rate. Functional assays showed that knockdown of MIAT inhibited renal cancer cell proliferation and metastasis in vitro and in vivo. Luciferase and western blot assays further confirmed that miR-29c binds with MIAT. Additionally, the correlation of miR-29c with MIAT and Loxl2 was further verified in patients' samples. Conclusion: Our data indicated that MIAT might be an oncogenic lncRNA that promoted proliferation and metastasis of ccRCC, and could be a potential therapeutic target in human ccRCC.
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Stamatopoulos, Basile, Nathalie Meuleman, Dominique Bron, Benjamin Haibe-Kains, Pascale Saussoy, Philippe Martiat, and Laurence Lagneaux. "MicroRNA-29c and 223 Are Powerful Prognostic Factors for Chronic Lymphocytic Leukemia and Improve Risk Stratification When Combined with ZAP70 and LPL in a qPCR Score." Blood 112, no. 11 (November 16, 2008): 1066. http://dx.doi.org/10.1182/blood.v112.11.1066.1066.
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Abstract Background: MicroRNAs (or miR) are a novel class of small noncoding RNA involved in gene regulation. Aberrant microRNA expression has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Currently, the heterogeneous evolution of this disease can be predicted by several prognostic factors. Nevertheless, a better individualization of the outcome in a given patient is still of utmost interest. Methods: In the current study, we investigated the expression of two microRNAs, miR-29c and miR-223, compared them to other biological or clinical markers and proposed a quantitative real-time PCR (qPCR) score to better assess CLL outcome. All cut-offs were calculated by ROC curve analysis maximising the correlation with the immunoglobulin variable heavy chain (IgVH) mutational status; statistical differences were evaluated by Mann Whitney test or Kruskal-Wallis test ; treatment-free (TFS) and overall (OS) survival differences were investigated by log-rank test or Cox proportional hazard ratio (HR). Results: miR-29c and miR-223 expression decreased significantly with progression along Binet Stage A to C (P=0.0010 and P=0.0183, respectively), and were significantly lower in poor prognosis subgroups defined by cytogenetic abnormalities, IgVH mutational status, lymphocyte doubling time, solubleCD23, β2-microglobulin, ζ-associated protein 70 (ZAP70), lipoprotein lipase (LPL) and CD38 expression. Furthermore, miR-29c and miR-223 could predict TFS (n=110, P=0.0015 and P<0.0001, respectively) and OS (n=110, P=0.0234 and P=0.0008, respectively). Regarding all these results, we developed a qPCR score (from 0 to 4 poor prognostic markers) combining miR-29c, miR-223, ZAP70 and LPL in order to stratify treatment and death risk in a 110 patient cohort with a median follow-up of 72 months (range, 2–312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of >312, 129, 80, 36 and 19 months, respectively (HR=17.00, P<0.0001). Patient with a score of 0–1/4, 2–3/4 and 4/4 had a median OS of >312, 183 and 106 months, respectively (HR=13.69, P=0.0001). Interestingly, during the first 50 months after diagnosis, only 10% of patients with a 0/4 score required a treatment, when compared to 100% of the 4/4. Furthermore, during the total follow-up (312 months), patients with a 4/4 score had a 27-fold higher risk to be treated and a 31-fold higher risk to die comparing to patients with a 0/4 score. This score was validated by a 10-fold cross-validation (prediction accuracy of 82%). Finally, in Binet stage A patients (n=77), this score remained relevant and significant for TFS and OS prediction (HR=18.56, P<0.0001 and HR=12.5, P=0.0068, respectively). Conclusions: we showed that (i) miR-29c and miR-223 levels were decreased in poor prognosis patients regarding several well-known prognostic factors; (ii) a low level of these two microRNAs is thus associated to disease aggressiveness, tumor burden and poor clinical evolution; (iii) we also showed that these two microRNAs could predict TFS and OS; (iv) we proposed a qPCR score to better individualize evolution of a particular CLL patient. This score will help to identify patients who will need early therapy and require thus a closer follow-up.
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Lin, Jianhong, Jianjun Zhao, Tint Lwin, Sophie Dessureault, Lynn C. Moscinski, William S. Dalton, Eduardo Sotomayor, Jin Cheng, and Jianguo Tao. "Use of MicroRNA Expression Profiling to Identify Prognostic Subclasses in Mantle Cell Lymphoma: Mir-29 Family as New Prognostic Markers." Blood 112, no. 11 (November 16, 2008): 3744. http://dx.doi.org/10.1182/blood.v112.11.3744.3744.
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Abstract Patients with mantle cell lymphoma (MCL) are typically older adults with a male predominance and usually present with stage IV disease. Response to chemotherapy usually results in a tumor response but remissions are short. It carries the poorest prognosis among non-Hodgkin’s lymphoma subtypes and the median survival is 3 to 4 years. However, recent clinical observations have identified variable clinical courses of MCL patients: some patients succumb rapidly to the disease, while others have a more chronic course and may not require treatment for prolonged periods of time. Given this clinical heterogeneity, we performed microRNA expression profiling on 34 mantle cell lymphoma (MCL) biopsy specimens to elucidate its pathogenesis and develop prognostic markers for survival of MCL patients. We identified downregulation of 18 miRNAs and upregulation of 22 miRNAs in MCL when compared with normal peripheral blood B lymphocytes, which is closely associated with molecular abnormalities. Furthermore, we found that expression levels of miR-29 family (miR-29a, miR-29b and miR-29c) were inversely correlated with MCL patient survival. A strong correlation between miR-29a, miR-29b and miR-29c values and newly described prognostic index for MCL patients, MIPI is identified. This first microRNA profling in MCL demonstrated that the miR-29a-c could be useful biomarkers for MCL prognosis and aberrant miRNA expression could contribute molecular MCL oncogenesis.
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Solé, Moliné, Vidal, Ordi-Ros, and Cortés-Hernández. "An Exosomal Urinary miRNA Signature for Early Diagnosis of Renal Fibrosis in Lupus Nephritis." Cells 8, no. 8 (July 25, 2019): 773. http://dx.doi.org/10.3390/cells8080773.
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For lupus nephritis (LN) management, it is very important to detect fibrosis at an early stage. Urinary exosomal miRNAs profiling can be used as a potential multi-marker phenotyping tool to identify early fibrosis. We isolated and characterised urinary exosomes and cellular pellets from patients with biopsy-proven LN (n = 45) and healthy controls (n = 20). LN chronicity index (CI) correlated with urinary exosomal miR-21, miR-150, and miR-29c (r = 0.565, 0.840, −0.559, respectively). This miRNA profile distinguished low CI from moderate-high CI in LN patients with a high sensitivity and specificity (94.4% and 99.8%). Furthermore, this multimarker panel predicted an increased risk of progression to end-stage renal disease (ESRD). Pathway analysis identified VEGFA and SP1 as common target genes for the three miRNAs. Immunohistochemistry in LN renal biopsies revealed a significant increase of COL1A1 and COL4A1 correlated with renal chronicity. SP1 decreased significantly in the high-CI group (p = 0.002). VEGFA levels showed no differences. In vitro experiments suggest that these miRNA combinations promote renal fibrosis by increasing profibrotic molecules through SP1 and Smad3/TGFβ pathways. In conclusion, a urinary exosomal multimarker panel composed of miR-21, miR-150, and miR-29c provides a non-invasive method to detect early renal fibrosis and predict disease progression in LN.
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Kunc, Michał, Marta Popęda, Anna Szałkowska, Magdalena Niemira, Michał Bieńkowski, Rafał Pęksa, Aleksandra Łacko, et al. "microRNA Expression Profile in Single Hormone Receptor-Positive Breast Cancers Is Mainly Dependent on HER2 Status—A Pilot Study." Diagnostics 10, no. 9 (August 20, 2020): 617. http://dx.doi.org/10.3390/diagnostics10090617.
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Estrogen (ER) and progesterone (PgR) receptors and HER2 are crucial in the assessment of breast cancer specimens due to their prognostic and predictive significance. Single hormone receptor-positive breast cancers are less common and their clinical course is less favorable than ER(+)/PgR(+) tumors. Their molecular features, especially microRNA (miRNA) profiles, have not been investigated to date. Tumor specimens from 36 chemonaive breast cancer patients with known ER and PgR status (18 ER(+)/PgR(−) and 18 ER(−)/PgR(+) cases) were enrolled to the study. The expression of 829 miRNAs was evaluated with nCounter Human v3 miRNA expression Assay (NanoString). miRNAs differentiating between ER/PgR/HER2 phenotypes were selected based on fold change (FC) calculated for the mean normalized counts of each probe in compared groups. The differences were estimated with Student’s t-test or Two-Way ANOVA (considering also the HER2 status). The results were validated using The Cancer Genome Atlas (TCGA) dataset. Following quality control of raw data, fourcases were excluded due to low sample quality, leaving 14 ER(+)/PgR(−) and 18 ER(−)/PgR(+) cases. After correction for multiple comparisons, we did not find miRNA signature differentiating between ER(−)/PgR(+) and ER(+)/PgR(−) breast cancers. However, a trend for differing expression (p-value ≤ 0.05; FDR > 0.2; ANOVA) in eight miRNAs was observed. The ER(+)/PgR(−) group demonstrated elevated levels of four miRNAs—miR-30a-5p, miR-29c-3p, miR-141-3p and miR-423-5p—while the ER(−)/PgR(+) tumors were enriched in another four miRNAs—miR-514b-5p, miR-424-5p, miR-495-3p, and miR-92a-3p. For one of the miRNAs—miR-29c-3p—the association with the ER(+)/PgR(−) phenotype was confirmed in the TCGA cohort (p-value = 0.024; t-test). HER2 amplification/overexpression in the NanoString cohort was related to significant differences observed in 33 miRNA expression levels (FDR ≤ 0.2; ANOVA). The association with HER2 status was confirmed in the TCGA cohort for four miRNAs (miR-1180-3p, miR-223-3p, miR-30d-5p, and miR-195-5p). The main differences in miRNA expression amongst single hormone receptor-positive tumors were identified according to their HER2 status. However, ER(+)/PgR(−) cases tended to express higher levels of miRNAs associated with ER-positivity (miR-30a-5p, miR-29c-3p, miR-141-3p), whereas ER(−)/PgR(+) cancers showed elevated levels of miRNAs characteristic for double- and triple-negative tumors (miR-92a-3p, miR-424-5p). Further studies are necessary to comprehensively analyze miRNA signatures characteristic of ER(−)/PgR(+) and ER(+)/PgR(−) tumors.
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Lin, Jianhong, Jianjun Zhao, Tint Lwin, Crespo Luis, Fangxia Guan, Sophie Dessureault, Lynn C. Moscinski, et al. "MiR-29 MicroRNAs Regulate IGF-1R Expression and Contribute Mantle Cell Lymphoma Growth and Survival." Blood 114, no. 22 (November 20, 2009): 1957. http://dx.doi.org/10.1182/blood.v114.22.1957.1957.
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Abstract Abstract 1957 Poster Board I-980 Mantle cell lymphoma (MCL) is now recognized as a distinct clinicopathologic subtype of B-cell lymphomas and carries the poorest prognosis among NHL subtypes with a median survival is 3 to 4 years. Clearly better understanding of MCL oncogenesis and novel therapeutic approaches to treating MCL are needed. Mounting evidence now shows that small noncoding microRNAs (miRNAs) can play roles as oncogenes or tumor suppressor genes, suggesting their contribution to cancer development and progression. Here, we for the first time, demonstrated that that miR-29a-c is frequently deleted or down-regulated and IGF-1R is often over-expressed in primary mantle cell lymphoma cells. Expression of miR-29 inversely correlates with the expression of IGF-1R. Consistent with these results, 1) overexpression of miR-29-c down-regulated IGF-R1, 2) overexpression of miR-29c inhibited cell growth, colony formation and induced cell cycle arrest in MCL cells, 3) depletion of miR-29-c by anti-miR29-c increased the threshold for apoptosis, 4) enforced expression of miR-29c suppressed MCL growth and tumor progression in NOD/SCID mouse xenograft models, 5) miR-29 directly regulates IGF-1R expression . Furthermore cell cycle arrest induced by these miRNAs depends on the expression of IGF-1R. Our results indicate that miR-29a-c are implicated in MCL cell cycle control, survival and likely contribute to the tumorigenesis of MCL. Disclosures: No relevant conflicts of interest to declare.
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Garavelli, Silvia, Sara Bruzzaniti, Elena Tagliabue, Francesco Prattichizzo, Dario Di Silvestre, Francesco Perna, Lucia La Sala, et al. "Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity." International Journal of Molecular Sciences 21, no. 2 (January 11, 2020): 477. http://dx.doi.org/10.3390/ijms21020477.
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Immune cell subsets and microRNAs have been independently proposed as type 1 diabetes (T1D) diagnostic and/or prognostic biomarkers. Here, we aimed to analyze the relationships between peripheral blood circulating immune cell subsets, plasmatic microRNAs, and T1D. Blood samples were obtained from both children with T1D at diagnosis and age-sex matched healthy controls. Then, immunophenotype assessed by flow cytometry was coupled with the quantification of 60 plasmatic microRNAs by quantitative RT-PCR. The associations between immune cell frequency, plasmatic microRNAs, and the parameters of pancreatic loss, glycemic control, and diabetic ketoacidosis were assessed by logistic regression models and correlation analyses. We found that the increase in specific plasmatic microRNAs was associated with T1D disease onset (let-7c-5p, let-7d-5p, let-7f-5p, let-7i-5p, miR-146a-5p, miR-423-3p, and miR-423-5p), serum C-peptide concentration (miR-142-5p and miR-29c-3p), glycated hemoglobin (miR-26a-5p and miR-223-3p) and the presence of ketoacidosis (miR-29c-3p) more strongly than the evaluated immune cell subset frequency. Some of these plasmatic microRNAs were shown to positively correlate with numbers of blood circulating B lymphocytes (miR-142-5p) and CD4+CD45RO+ (miR-146a-5p and miR-223-3p) and CD4+CD25+ cells (miR-423-3p and miR-223-3p) in children with T1D but not in healthy controls, suggesting a disease-specific microRNA association with immune dysregulation in T1D. In conclusion, our results suggest that, while blood co-circulating extracellular microRNAs and immune cell subsets may be biologically linked, microRNAs may better provide powerful information about T1D onset and severity.
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Kozłowska, Małgorzata, and Agnieszka Śliwińska. "The Link between Diabetes, Pancreatic Tumors, and miRNAs—New Players for Diagnosis and Therapy?" International Journal of Molecular Sciences 24, no. 12 (June 16, 2023): 10252. http://dx.doi.org/10.3390/ijms241210252.
Full textAbstract:
Despite significant progress in medicine, pancreatic cancer is one of the most tardily diagnosed cancer and is consequently associated with a poor prognosis and a low survival rate. The asymptomatic clinical picture and the lack of relevant diagnostic markers for the early stages of pancreatic cancer are believed to be the major constraints behind an accurate diagnosis of this disease. Furthermore, underlying mechanisms of pancreatic cancer development are still poorly recognized. It is well accepted that diabetes increases the risk of pancreatic cancer development, however the precise mechanisms are weakly investigated. Recent studies are focused on microRNAs as a causative factor of pancreatic cancer. This review aims to provide an overview of the current knowledge of pancreatic cancer and diabetes-associated microRNAs, and their potential in diagnosis and therapy. miR-96, miR-124, miR-21, and miR-10a were identified as promising biomarkers for early pancreatic cancer prediction. miR-26a, miR-101, and miR-200b carry therapeutic potential, as they not only regulate significant biological pathways, including the TGF-β and PI3K/AKT, but their re-expression contributes to the improvement of the prognosis by reducing invasiveness or chemoresistance. In diabetes, there are also changes in the expression of microRNAs, such as in miR-145, miR-29c, and miR-143. These microRNAs are involved, among others, in insulin signaling, including IRS-1 and AKT (miR-145), glucose homeostasis (hsa-miR-21), and glucose reuptake and gluconeogenesis (miR-29c). Although, changes in the expression of the same microRNAs are observed in both pancreatic cancer and diabetes, they exert different molecular effects. For example, miR-181a is upregulated in both pancreatic cancer and diabetes mellitus, but in diabetes it contributes to insulin resistance, whereas in pancreatic cancer it promotes tumor cell migration, respectively. To conclude, dysregulated microRNAs in diabetes affect crucial cellular processes that are involved in pancreatic cancer development and progression.
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Lopez, Navita N., Rajiv Rangan, Abbot F. Clark, and Tara Tovar-Vidales. "Mirna Expression in Glaucomatous and TGFβ2 Treated Lamina Cribrosa Cells." International Journal of Molecular Sciences 22, no. 12 (June 8, 2021): 6178. http://dx.doi.org/10.3390/ijms22126178.
Full textAbstract:
Glaucoma is a group of optic neuropathies that leads to irreversible vision loss. The optic nerve head (ONH) is the site of initial optic nerve damage in glaucoma. ONH-derived lamina cribrosa (LC) cells synthesize extracellular matrix (ECM) proteins; however, these cells are adversely affected in glaucoma and cause detrimental changes to the ONH. LC cells respond to mechanical strain by increasing the profibrotic cytokine transforming growth factor-beta 2 (TGFβ2) and ECM proteins. Moreover, microRNAs (miRNAs or miR) regulate ECM gene expression in different fibrotic diseases, including glaucoma. A delicate homeostatic balance between profibrotic and anti-fibrotic miRNAs may contribute to the remodeling of ONH. This study aimed to determine whether modulation of miRNAs alters the expression of ECM in human LC cells. Primary human normal and glaucoma LC cells were grown to confluency and treated with or without TGFβ2 for 24 h. Differences in expression of miRNAs were analyzed using miRNA qPCR arrays. miRNA PCR arrays showed that the miR-29 family was significantly decreased in glaucomatous LC cell strains compared to age-matched controls. TGFβ2 treatment downregulated the expression of multiple miRNAs, including miR-29c-3p, compared to controls in LC cells. LC cells transfected with miR-29c-3p mimics or inhibitors modulated collagen expression.
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Zeng, Xi, Juanjuan Xiang, Minghua Wu, Wei Xiong, Hailin Tang, Min Deng, Xiayu Li, et al. "Circulating miR-17, miR-20a, miR-29c, and miR-223 Combined as Non-Invasive Biomarkers in Nasopharyngeal Carcinoma." PLoS ONE 7, no. 10 (October 8, 2012): e46367. http://dx.doi.org/10.1371/journal.pone.0046367.
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