Deletion of pancreas-specific miR-216a reduces beta-cell mass and inhibits pancreatic cancer progression in mice

Erener, Süheda; Ellis, Cara; Ramzy, Adam; Glavas, Maria M.; O’Dwyer, Shannon; Pereira, Sandra; Wang, Tom; Pang, Janice; Bruin, Jennifer E.; Riedel, Michael; Baker, Robert K.; Webber, Travis D.; Lesina, Marina; Blüher, Matthias; Algül, Hana; Kopp, Janel L.; Herzig, Stephan; Kieffer, Timothy J.

doi:10.1016/j.xcrm.2021.100434

Cited by 13 publications

(11 citation statements)

References 85 publications

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“…Additionally, this cluster has been established as a potential diagnostic and prognostic biomarker for various carcinomas such as ovarian cancer (Gao et al 2015 ), breast cancer (Choi et al 2016 ), and lung adenocarcinoma (Tejero et al 2014 ). Although the prognostic impact of hsa-mir-216a/mir-217 and hsa-mir-15b/mir-16-2 candidates’ dysregulation has been confirmed in several types of cancers (Aqeilan et al 2010 ; Lovat et al 2015 ; Azevedo-Pouly et al 2017 ; Erener et al 2021 ). However, there is no explicit evidence for these clusters can be used as a marker for BCa diagnosis.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and prognostic potential clustered miRNAs in bladder cancer

et al. 2022

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At specific genomic loci, miRNAs are in clusters and their association with copy number variations (CNVs) may exhibit abnormal expression in several cancers. Hence, the current study aims to understand the expression of miRNA clusters residing within CNVs and the regulation of their target genes in bladder cancer. To achieve this, we used extensive bioinformatics resources and performed an integrated analysis of recurrent CNVs, clustered miRNA expression, gene expression, and drug–gene interaction datasets. The study identified nine upregulated miRNA clusters that are residing on CNV gain regions and three miRNA clusters (hsa-mir-200c/mir-141, hsa-mir-216a/mir-217, and hsa-mir-15b/mir-16-2) are correlated with patient survival. These clustered miRNAs targeted 89 genes that were downregulated in bladder cancer. Moreover, network and gene enrichment analysis displayed 10 hub genes (CCND2, ETS1, FGF2, FN1, JAK2, JUN, KDR, NOTCH1, PTEN, and ZEB1) which have significant potential for diagnosis and prognosis of bladder cancer patients. Interestingly, hsa-mir-200c/mir-141 and hsa-mir-15b/mir-16-2 cluster candidates showed significant differences in their expression in stage-specific manner during cancer progression. Downregulation of NOTCH1 by hsa-mir-200c/mir-141 may also sensitize tumors to methotrexate thus suggesting potential chemotherapeutic options for bladder cancer subjects. To overcome some computational challenges and reduce the complexity in multistep big data analysis, we developed an automated pipeline called CmiRClustFinder v1.0 (https://github.com/msls-bioinfo/CmiRClustFinder_v1.0), which can perform integrated data analysis of 35 TCGA cancer types.

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Section: Discussionmentioning

confidence: 99%

Diagnostic and prognostic potential clustered miRNAs in bladder cancer

et al. 2022

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“…For example, we find HPI levels of miR-216a and miR-25 to be negatively and positively correlated with HbA1c genetic scores, respectively. In previous work, the miR-216a knockout mouse was reported to have defects in insulin secretion in the context of chronic high-fat diet (77), and miR-25 has been described as a negative regulator of insulin synthesis in INS-1 cells, a rat beta cell line (64). As another example, we show that miR-199b-5p is associated with T2D status, consistent with a previous study in murine beta cells where miR-199b-5p was shown to be highly responsive to glucose stimulation (78).…”

Section: Discussionmentioning

confidence: 99%

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Taylor¹,

Hung

Narisu³

et al. 2022

Preprint

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Genetic studies have identified ≥240 loci associated with risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, representing the largest sequencing-based analysis of miRNA expression in human islets to date. We characterize the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans-acting genetic components and mapping cis-acting loci associated with miRNA expression (miRNA-eQTLs). We find (i) 81 heritable miRNAs, primarily regulated by trans-acting genetic effects, and (ii) 5 miRNA-eQTLs. We also use several different strategies to identify T2D-associated miRNAs. First, we colocalize miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersect miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and find 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we perform differential expression analysis and identify 13 miRNAs associated with T2D status—including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p—and 4 miRNAs associated with a polygenic score for HbA1c levels—miR-216a, miR-25, miR-30a-3p, and miR-30a-5p.

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“…For example, we find HPI levels of miR-216a and miR-25 to be negatively and positively correlated with HbA1c genetic scores, respectively. In previous work, the miR-216a knockout mouse was reported to have defects in insulin secretion in the context of chronic high-fat diet ( 90 ), and miR-25 has been described as a negative regulator of insulin synthesis in INS-1 cells, a rat insulinoma cell line ( 75 ). As another example, we show that miR-199b-5p is associated with T2D status, consistent with a previous study in murine beta cells where miR-199b-5p was shown to be highly responsive to glucose stimulation ( 91 ).…”

Section: Discussionmentioning

confidence: 99%

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Taylor

Hung

Narisu

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Genetic studies have identified ≥240 loci associated with the risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, the largest sequencing-based analysis of miRNA expression in human islets to date. We characterized the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans- acting genetic components and mapping cis -acting loci associated with miRNA expression [miRNA-expression quantitative trait loci (eQTLs)]. We found i) 84 heritable miRNAs, primarily regulated by trans -acting genetic effects, and ii) 5 miRNA-eQTLs. We also used several different strategies to identify T2D-associated miRNAs. First, we colocalized miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersected miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and found 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we performed differential expression analysis and identified 14 miRNAs associated with T2D status—including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p—and 4 miRNAs associated with a polygenic score for HbA1c levels—miR-216a, miR-25, miR-30a-3p, and miR-30a-5p.

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Deletion of pancreas-specific miR-216a reduces beta-cell mass and inhibits pancreatic cancer progression in mice

Cited by 13 publications

References 85 publications

Diagnostic and prognostic potential clustered miRNAs in bladder cancer

Diagnostic and prognostic potential clustered miRNAs in bladder cancer

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

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