Altering β-cell number through stable alteration of miR-21 and miR-34a expression

Backe, Marie Balslev; Novotny, Guy Wayne; Christensen, Dan Ploug; Grunnet, Lars Groth; Mandrup-Poulsen, Thomas

doi:10.4161/isl.27754

Cited by 44 publications

(43 citation statements)

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“…More recent work reported increased beta cell apoptosis after stable lentiviral miR-21 overexpression. However, the authors did not observe concurrent reductions in PDCD4 with miR-21 overexpression, or identify a mechanism explaining the potential proapoptotic effects of miR-21 [14], leaving a number of unresolved controversies regarding the effect of miR-21 on beta cell survival and function.…”

Section: Discussionmentioning

confidence: 99%

“…This miRNA has been well characterised in other cell types, and has been classically been labelled an ‘oncomiR’ in cancer cells, due to the inhibition of tumour suppressor genes, which produces pro-survival effects [16–18]. However, the role of miR-21 in beta cells has been less clear, with conflicting data regarding pro-survival vs proapoptotic effects [13, 14, 19]. Using human islets and cell line models of type 1 diabetes, we sought here to define the context of beta cell miR-21 upregulation and the phenotype of beta cell miR-21 overexpression by novel target identification.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells

et al. 2017

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Aims/hypothesis The role of beta cell microRNA (miR)-21 in the pathophysiology of type 1 diabetes has been controversial. Here, we sought to define the context of beta cell miR-21 upregulation in type 1 diabetes and the phenotype of beta cell miR-21 overexpression through target identification. Methods Islets were isolated from NOD mice and mice treated with multiple low doses of streptozotocin, as a mouse model of diabetes. INS-1 832/13 beta cells and human islets were treated with IL-1β, IFN-γ and TNF-α to mimic the milieu of early type 1 diabetes. Cells and islets were transfected with miR-21 mimics or inhibitors. Luciferase assays and polyribosomal profiling (PRP) were performed to define miR-21–target interactions. Results Beta cell miR-21 was increased in in vivo models of type 1 diabetes and cytokine-treated cells/islets. miR-21 overexpression decreased cell count and viability, and increased cleaved caspase 3 levels, suggesting increased cell death. In silico prediction tools identified the antiapoptotic mRNA BCL2 as a conserved miR-21 target. Consistent with this, miR-21 overexpression decreased BCL2 transcript and B Cell lymphoma 2 (BCL2) protein production, while miR-21 inhibition increased BCL2 protein levels and reduced cleaved caspase 3 levels after cytokine treatment. miR-21-mediated cell death was abrogated in 828/33 cells, which constitutively overexpress Bcl2. Luciferase assays suggested a direct interaction between miR-21 and the BCL2 3′ untranslated region. With miR-21 overexpression, PRP revealed a shift of the Bcl2 message towards monosome-associated fractions, indicating inhibition of Bcl2 translation. Finally, overexpression in dispersed human islets confirmed a reduction in BCL2 transcripts and increased cleaved caspase 3 production. Conclusions/interpretation In contrast to the pro-survival role reported in other systems, our results demonstrate that miR-21 increases beta cell death via BCL2 transcript degradation and inhibition of BCL2 translation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells

et al. 2017

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“…miR-34a is also linked to metabolic function and the development of diabetes. Specifically, miR-34a has been shown to increase the apoptosis of β-cells, possibly increasing susceptibility to diabetes[98,99]. These studies suggest that, while beneficial in the cancerous setting, miR-34a’s pro-senescence and pro-apoptotic role in other tissues could disrupt normal function.…”

Section: Delivery Of Mirna Therapeuticsmentioning

confidence: 99%

The tumor-suppressive and potential therapeutic functions of miR-34a in epithelial carcinomas

Adams

Parsons

Slack

2015

Expert Opinion on Therapeutic Targets

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Introduction Many RNA species have been identified as important players in the development of chronic diseases including cancer. Certain classes of regulatory RNAs such as miRNAs have been investigated in such detail that bona fide tumor suppressive and oncogenic miRNAs have been identified. Because of this, there has been a major effort to therapeutically target these small RNAs. One in particular, a liposomal formulation of miR-34a (MRX34), has entered Phase I trials. Areas Covered This review aims to summarize miRNA biology, its regulation within normal versus disease states, and how it can be targeted therapeutically, with a particular emphasis on miR-34a. Understanding the complexity of a single miRNA will aid in the development of future RNA-based therapeutics for a broader range of chronic diseases. Expert Opinion The potential of miRNAs to be developed into anti-cancer therapeutics has become an increasingly important area of research. miR-34a is a tumor suppressive miRNA across many tumor types through its ability to inhibit cellular proliferation, invasion, and tumor sphere formation. miR-34a also shows promise within certain in vivo solid tumor models. Finally, as miR-34a moves into clinical trials it will be important to determine if it can further sensitize tumors to certain chemotherapeutic agents.

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“…Several other miRNAs, including miR-9, miR-124a, miR-126, miR-34a, and miR21, have been studied for their roles in glucose regulation or pancreatic β cell function; however, there are few studies on their therapeutic effects for diabetes mellitus [1,73–77]. Further studies on the effects of gene therapies using targeted miRNA for the treatment of diabetes mellitus in vivo are required.…”

Section: Other Transgenesmentioning

confidence: 99%

Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus

Ookawara

Ishibashi

et al. 2017

Nano Reviews & Experiments

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Gene therapy that targets the pancreas and intestines with delivery systems using nano-sized carriers such as viral and non-viral vectors could improve the control of blood glucose levels, resulting in an improved prognosis for patients with diabetes mellitus. Allogenic pancreatic islet cell transplantations using such delivery systems have been developed as therapeutic options for diabetes mellitus. This review focuses on transgenes and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus.

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Altering β-cell number through stable alteration of miR-21 and miR-34a expression

Cited by 44 publications

References 46 publications

MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells

MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells

The tumor-suppressive and potential therapeutic functions of miR-34a in epithelial carcinomas

Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus

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