MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer

Hao, Jun; Zhang, Shuyu; Zhou, Yingqi; Hu, Xinyu; Shao, Chenghao

doi:10.1016/j.febslet.2010.11.039

Cited by 97 publications

(100 citation statements)

References 36 publications

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“…Inhibition of miR-27a was shown to inhibit growth, colony formation and migration of pancreatic cancer cells [105]. Likewise, anti-miR-483-3p transfection in SW1990 and PANC-1 cells significantly reduced cell proliferation and colony formation [103]. Another study showed that anti-miR-371-5p treatment causes proliferative inhibition of pancreatic cancer cells, which is partially due to a G1-phase arrest [106].…”

Section: • Strategies Blocking Mirna Functionsmentioning

confidence: 95%

Developments in miRNA gene signaling pathways in pancreatic cancer

2016

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Pancreatic cancer is a devastating malignancy that ranks as the fourth leading cause of cancerrelated deaths worldwide. Dismal prognosis is mainly attributable to limited knowledge of the molecular pathogenesis of the disease. miRNAs have been found to be deregulated in pancreatic cancer, affecting several steps of initiation and aggressiveness of the disease by regulating important signaling pathways, such as the KRAS and Notch pathways. Moreover, the effect of miRNAs on regulating cell cycle events and expression of transcription factors has gained a lot of attention. Recent studies have highlighted the application of miRNAs as biomarkers and therapeutic tools. The current review focuses on latest advances with respect to the roles of miRNAs in pancreatic ductal adenocarcinoma associated signaling pathways and miRNA-based therapeutics. KEYWORDS• antisense oligonucleotides • miRNAs • pancreatic cancer Pancreatic cancer overview Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic neoplasms and accounts for greater than 85% of the clinical cases [1]. The disease develops via acinar-ductal metaplasia and neoplastic precursor lesions [2]. In the USA alone, 48,960 new cases of pancreatic cancer were expected to occur in 2015, with an estimated 40,560 deaths, about the same number in women (19,850) as in men (20,710). Over 96% are cancers arising from exocrine pancreas. Endocrine carcinomas are often diagnosed at a younger age and exhibit a better prognosis. From 2007 to 2011, mortality rates increased slightly by 0.3% per year. For all stages combined, the 1-and 5-year relative survival rates are 28 and 7%, respectively. For the small percentage of people diagnosed with local disease (9%), the 5-year survival is 26%, while more than half of patients (53%) are diagnosed at a late stage for which 1-and 5-year survival rates reach 15 and 2%, respectively [3]. These numbers are a staggering example of the poor prognosis associated with PDAC.While new therapeutic options are emerging for nonhematologic malignancies, molecular-targeted therapies for pancreatic cancer have failed to make any positive impact on patient survival. In 1993, the Nobel Prize-winning discovery of small interference RNAs (siRNAs) led to an outburst of knowledge on RNA interference and gene regulation [4]. Since then, thousands of research studies have described the functional role of small noncoding RNAs, named miRNAs, in a vast panel of human pathologies. In 2002, a small genomic region in chromosome 13q14 comprising miR-15a and miR-16-1 genes was found to be commonly deleted in chronic lymphocytic leukemia, For reprint orders, please contact: reprints@futuremedicine.com

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Section: • Strategies Blocking Mirna Functionsmentioning

confidence: 95%

Developments in miRNA gene signaling pathways in pancreatic cancer

2016

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“…44 In pancreatic cancer, miR-483-3p was found to target DPC4/Smad4, and their expression levels are inversely correlated in human pancreatic cancer tissues. 45 Given the potential involvement of miR-483-3p in the response to oxidative stress in HTMCs and the relevance of TGF-b/Smad signaling in the pathogenic responses induced by oxidative stress, we analyzed the influence of miR-483-3p on gene expression in HTMC, and found that miR-483-3p induced significant changes in expression of several genes involved in ECM deposition, including fibronectin, collagen, and laminin.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

Shen

Han

Huang

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. This study investigated the effects of microRNA-483-3p (miR-483-3p) on extracellular matrix (ECM) production, and clarified the regulatory mechanism of microRNA-483-3p in human trabecular meshwork cells (HTMCs) under oxidative stress. METHODS.The expression levels of ECM (fibronectin, laminin, collagen I) in HTMCs under oxidative stress were measured by Western blot. Changes of miR-483-3p expression in HTMCs were evaluated by quantitative polymerase chain reaction (qPCR). After using lentivirus stably expressing pri-miR-483, the effects of miR-483-3p on the ECM were assessed by qPCR and Western blot. Smad4, the potential target of miR-483-3p according to mRNA target-predicting algorithms, was confirmed by luciferase assay and Western blot. Furthermore, the effects of Smad4 knockdown on ECM expression were investigated by qPCR and Western blot.RESULTS. The mRNA and protein levels of ECM (fibronectin, laminin, collagen I) were upregulated in HTMCs induced by oxidative stress. The expression level of miR-483-3p decreased in HTMCs under oxidative stress, and the ectopic expression of miR-483-3p decreased the levels of ECM. In addition, miR-483-3p targeted Smad4 through two binding sites, resulting in a decrease of Smad4 expression. Furthermore, knockdown of Smad4 reduced the levels of ECM in HTMCs.CONCLUSIONS. MicroRNA-483-3p has an inhibitory effect on ECM production in HTMCs through downregulating Smad4, which indicates that miR-483-3p may serve as a potential therapeutic target in glaucoma.

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“…13 Additional miR-483-3p target genes including BBC3/ PUMA, SMAD4, CTNNB1 and GDF3 have been identified in other tissues (Wilm's tumors, adrenocortical carcinomas, HCT116 colon and HepG2 hepatocellular carcinoma cell lines, and adipose tissue). [14][15][16][17][18] We demonstrate now that CDC25A has a key role in the mediation of the anti-proliferative effects of miR-483-3p in keratinocytes by controlling the binding between CDK6/4 and CCNDs. Our results obtained on CDK6 shed new light on the mechanisms that control CCND-CDK6/4 assembly in early G1, showing that this association greatly depends on the phosphorylation status of the Y residues located in the 'Glycin rich domain' of these kinases.…”

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confidence: 99%

CDC25A targeting by miR-483-3p decreases CCND–CDK4/6 assembly and contributes to cell cycle arrest

et al. 2013

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Disruption of contact inhibition and serum afflux that occur after a tissue injury activate cell cycle, which then stops when confluence is reached again. Although the events involved in cell cycle entry have been widely documented, those managing cell cycle exit have remained so far ill defined. We have identified that the final stage of wound closure is preceded in keratinocytes by a strong accumulation of miR-483-3p, which acts as a mandatory signal triggering cell cycle arrest when confluence is reached. Blocking miR-483-3p accumulation strongly delays cell cycle exit, maintains cells into a proliferative state and retards their differentiation program. Using two models of cell cycle synchronization (i.e. mechanical injury and serum addition), we show that an ectopic upregulation of miR-483-3p blocks cell cycle progression in early G1 phase. This arrest results from a direct targeting of the CDC25A phosphatase by miR-483-3p, which can be impeded using an anti-miRNA against miR-483-3p or a protector that blocks the complex formation between miR-483-3p and the 3 0 -untranslated region (UTR) of CDC25A transcript. We show that the miRNA-induced silencing of CDC25A increases the tyrosine phosphorylation status of CDK4/6 cyclin-dependent kinases which, in turn, abolishes CDK4/6 capacity to associate with D-type cyclins. This prevents CDK4/6 kinases' activation, impairs downstream events such as cyclin E stimulation and sequesters cells in early G1. We propose this new regulatory process of cyclin-CDK association as a general mechanism coupling miRNA-mediated CDC25A invalidation to CDK posttranscriptional modifications and cell cycle control.

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MicroRNA 483-3p suppresses the expression of DPC4/Smad4 in pancreatic cancer

Cited by 97 publications

References 36 publications

Developments in miRNA gene signaling pathways in pancreatic cancer

Developments in miRNA gene signaling pathways in pancreatic cancer

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

CDC25A targeting by miR-483-3p decreases CCND–CDK4/6 assembly and contributes to cell cycle arrest

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