miR-144/451 Promote Cell Proliferation via Targeting PTEN/AKT Pathway in Insulinomas

Jiang, Xin; Shan, Aijing; Su, Yutong; Cheng, Yulong; Gu, Weiqiong; Wang, Weiqing; Ning, Guang; Cao, Yanan

doi:10.1210/en.2014-1966

Cited by 40 publications

(41 citation statements)

References 38 publications

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“…It has been shown that PTEN is a direct downstream target of miR-216a in cancer 38,39 and kidney disorders 37 . In addition, multiple studies have previously demonstrated that PTEN deletion in beta cells leads to proliferation of these cells in vivo 27,[45][46][47][48] and protection from STZ-induced diabetes 49 . One study demonstrated that systemic administration of PTEN ASO suppressed PTEN mRNA, and normalized blood glucose in db/db and ob/ob mice 9 .…”

Section: Discussionmentioning

confidence: 99%

miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

Wang

Liu

Zhao

et al. 2020

Sci Rep

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Aberrant expression of miRNAs in pancreatic islets is closely related to the development of type 1 diabetes (T1D). The aim of this study was to identify key miRNAs dysregulated in pancreatic islets during T1D progression and to develop a theranostic approach to modify their expression using an MRI-based nanodrug consisting of iron oxide nanoparticles conjugated to miRNA-targeting oligonucleotides in a mouse model of T1D. Isolated pancreatic islets were derived from NOD mice of three distinct age groups (3, 8 and 18-week-old). Total RNA collected from cultured islets was purified and global miRNA profiling was performed with 3D-Gene global miRNA microarray mouse chips encompassing all mouse miRNAs available on the Sanger miRBase V16. Of the miRNAs that were found to be differentially expressed across three age groups, we identified one candidate (miR-216a) implicated in beta cell proliferation for subsequent validation by RT-PCR. Alterations in miR-216a expression within pancreatic beta cells were also examined using in situ hybridization on the frozen pancreatic sections. For in vitro studies, miR-216a mimics/inhibitors were conjugated to iron oxide nanoparticles and incubated with beta cell line, βTC-6. Cell proliferation marker Ki67 was evaluated. Expression of the phosphatase and tensin homolog (PTEN), which is one of the direct targets of miR-216a, was analyzed using western blot. For in vivo study, the miR-216a mimics/inhibitors conjugated to the nanoparticles were injected into 12-week-old female diabetic Balb/c mice via pancreatic duct. The delivery of the nanodrug was monitored by in vivo MRI. Blood glucose of the treated mice was monitored post injection. Ex vivo histological analysis of the pancreatic sections included staining for insulin, PTEN and Ki67. miRNA microarray demonstrated that the expression of miR-216a in the islets from NOD mice significantly changed during T1D progression. In vitro studies showed that treatment with a miR-216a inhibitor nanodrug suppressed proliferation of beta cells and increased the expression of PTEN, a miR-216a target. In contrast, introduction of a mimic nanodrug decreased PTEN expression and increased beta cell proliferation. Animals treated in vivo with a mimic nanodrug had higher insulinproducing functionality compared to controls. These observations were in line with downregulation of PTEN and increase in beta cell proliferation in that group. Our studies demonstrated that miR-216a could serve as a potential therapeutic target for the treatment of diabetes. miR-216a-targeting theranostic nanodrugs served as exploratory tools to define functionality of this miRNA in conjunction with in vivo MR imaging.

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Section: Discussionmentioning

confidence: 99%

miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

Wang

Liu

Zhao

et al. 2020

Sci Rep

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“…2 The miR-144/451 locus is directly regulated by multiple nuclear proteins. A 12-kb long 5′ flanking DNA sequence of miR-144/451 locus is annotated, with the positions of the binding sites relative to the transcription start given in kilobases being indicated in parentheses include hematopoietic malignancies [21,34,35,37], lung cancer [32,[66][67][68], glioblastoma [52,[69][70][71], breast cancer [33,72], colorectal cancer [73][74][75][76], gastric cancer [74], nasopharyngeal cancer [77,78], pancreatic cancer [79,80], and other tumors [42,81,82]. However, no in vivo studies had confirmed such observations until a recent in vivo study demonstrated that the deficiency of miR-144/451 gene expression is a driver of B-lymphomagenesis though the tumor suppressive activity is weak by miR-144/451 alone [21].…”

Section: Mir-144/451 In Tumorigenesismentioning

confidence: 99%

“…For example, miR-451 level is much lower in cancers from the digestive system [74,83], non-small cell lung carcinoma (NSCLC) tissues [67,68], and DLBCL [21]. While majority of studies indicate miR-144 or miR-451 as tumor suppressive miRNAs, several groups suggest that miR-144 or miR-451 inherits oncogenic activities [77,80], which is consistent with the prognosis studies that glioblastoma patients with high miR-451 levels in tumor cells have significantly short [21] miR-144 B-cell lymphoma BCL6 suppressive [37] miR-451 T cell acute lymphoblastic leukemia c-Myc suppressive [34] miR-451 multiple myeloma TSC1 suppressive [35] miR-451 lung cancer c-Myc suppressive [66] miR-451 lung cancer RAB14 suppressive [67] miR-451 lung cancer Akt suppressive [68] miR-451 lung cancer c-Myc suppressive [32] miR-451 glioblastoma c-Myc suppressive [69] miR-451 glioblastoma Cab39…”

Section: Mir-144/451 In Tumorigenesismentioning

confidence: 99%

miR-144/451 in hematopoiesis and beyond

Wang

2019

ExRNA

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MicroRNAs (miRNAs), a class of 18-25 nucleotide (nt) non-coding RNAs, usually inhibit the expression of their target genes. They are transcribed from endogenous genes and are processed for maturation by multiple pathways. miR-144/451, a bicistronic gene locus, encodes miR-144 and miR-451, both of which are highly conserved in evolution. These two miRNAs are on the same primary RNA molecule whose transcription is controlled by multiple nuclear proteins, including GATA1, GATA4, Myc, Oct1, Pax4, FXR, AP1, SMAD3 and SMAD4 depending on tissue types. They are abundant and almost exclusively exist in red blood cells, but low expression of both miR-144 and miR-451 are also detected in non-erythroid lineages. Interestingly, deletion of both miR-144 and miR-451 DNA sequences coding pre-miR-144/451 hairpins in mice leads only mild microcytic anemia but worsen upon a number of stresses including developmental stress, acute blood loss, phenohydrazine-induced hemolysis and precursor depletion by chemotherapeutic drug 5-FU. Such knockout animals older than 15 months also spontaneously develop malignant tumors including B-lymphoma and acute myeloid leukemia, indicating that miR-144/451 is a bona fide tumor-suppressing gene in non-erythroid cells, though its levels are much lower compared to that in red blood cells. Consistent with the findings in animals, disruption of miR-144/451 expression and their abnormal functions are observed in human hematopoietic and non-hematopoietic organs. Moreover, miR-451 is the only miRNA discovered so far whose maturation does not depend on Dicer, an enzyme required by all other miRNAs for maturation. This review focuses on the biogenesis, transcriptional regulation and biological roles of miR-144/451 in erythropoiesis, tumor initiation and other pathological conditions.

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“…MiR-144/451 was also studied in murine pancreatic β-cells, where it induced cell proliferation. In the MIN6 cell line, MiR-144 targeted PTEN and activated the AKT pathway in pancreatic β-cells, while MiR-451 targeted the cell cycle regulator P19 INK4D to promote pancreatic β-cell proliferation [52]. …”

Section: Tissue Expression Of Mirnas In Gep-netsmentioning

confidence: 99%

A Comprehensive Assessment of the Role of miRNAs as Biomarkers in Gastroenteropancreatic Neuroendocrine Tumors

et al. 2018

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Background/Aims: A key issue in neuroendocrine neoplasia management is the identification of blood signatures that specifically define the activity of a cancer or local tumor microenvironment. MicroRNAs (miRNAs) may represent such a candidate. To evaluate their clinical utility as biomarkers in gastroenteropancreatic neuroendocrine tumors (GEP-NETs), we assessed their expression in tissue and blood. Methods: A systematic review of PubMed was undertaken to identify studies investigating miRNAs in GEP-NETs and their utility as blood or tissue biomarkers. Results: Twenty-two studies using a range of methodologies with different normalization protocols were identified: tumor – gastric NET type 1 (n = 1 study: MiR-222, regulates p27KIP1), pancreatic (n = 6: MiR-21 [inflammatory marker, oncogene] and MiR-144 [PI₃K/AKT signaling], both up- and downregulated depending on the method), small intestinal (n = 7: no consistent signature), and colorectal (n = 3: no consistent signature); blood – gastric NET type 1 (n = 1: MiR-222), pancreatic (n = 3: MiR-21), and small intestinal (n = 3: no consistent signature). The studies all included heterogeneous cohorts, were insufficiently powered, and utilized different methodologies, and age- and gender-matched controls were not used. Different miRNA isolation methods and detection protocols resulted in inconsistent expression comparing tumor and blood. A scientific discrepancy was the downregulated expression of some circulating candidates compared to tissue levels, suggesting methodological issues or physiological responses to the tumor. Both are of concern in defining the biometrics of a marker. Conclusions: A potential biomarker for GEP-NETs included MiR-21 (small bowel and pancreas), but this epithelial tumor marker requires prospective validation. Overall, significant scientific investigation remains to identify and demonstrate neuroendocrine specificity and to validate candidate miRNA biomarkers.

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miR-144/451 Promote Cell Proliferation via Targeting PTEN/AKT Pathway in Insulinomas

Cited by 40 publications

References 38 publications

miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

miR-216a-targeting theranostic nanoparticles promote proliferation of insulin-secreting cells in type 1 diabetes animal model

miR-144/451 in hematopoiesis and beyond

A Comprehensive Assessment of the Role of miRNAs as Biomarkers in Gastroenteropancreatic Neuroendocrine Tumors

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