High levels of onco-miR-21 contribute to the senescence-induced growth arrest in normal human cells and its knock-down increases the replicative lifespan

Dellago, Hanna; Preschitz-Kammerhofer, Barbara; Terlecki‐Ζaniewicz, Lucia; Schreiner, Carina; Fortschegger, Klaus; Chang, Martina; Hackl, Matthias; Monteforte, Rossella; Kühnel, Harald; Schosserer, Markus; Грубер, Флориан; Tschachler, Erwin; Scheideler, Marcel; Grillari‐Voglauer, Regina; Grillari, Johannes; Wieser, Matthias

doi:10.1016/j.exger.2015.01.019

Cited by 8 publications

(11 citation statements)

References 38 publications

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“…In this study, we focus on the colorectal cancer cells' migration and invasion and investigate that MDE downregulate BRG1 through miR-21-5p and miR-155-5p and promote cell migration and invasion in colon cancer. Furthermore, there is also a published paper showing that high levels of oncomiR-21 contribute to the senescence-induced growth arrest in normal human cells (54), which supports our conclusion. However, in this study, we did not examine exosomes derived from the tumor cells to macrophages.…”

Section: Discussionsupporting

confidence: 89%

M2 Macrophage-Derived Exosomes Promote Cell Migration and Invasion in Colon Cancer

et al. 2019

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Clinical and experimental evidence has shown that tumorassociated macrophages promote cancer initiation and progression. However, the macrophage-derived molecular determinants that regulate colorectal cancer metastasis have not been fully characterized. Here, we demonstrate that M2 macrophage-regulated colorectal cancer cells' migration and invasion is dependent upon M2 macrophage-derived exosomes (MDE). MDE displayed a high expression level of miR-21-5p and miR-155-5p, and MDE-mediated colorectal cancer cells' migration and invasion depended on these two miRNAs. Mechanistically, miR-21-5p and miR-155-5p were transferred to colorectal cancer cells by MDE and bound to the BRG1 coding sequence, downregulating expression of BRG1, which has been identified as a key factor promoting the colorectal cancer metastasis, yet is downregulated in metastatic colorectal cancer cells. Collectively, these findings show that M2 macrophages induce colorectal cancer cells' migration and invasion and provide significant plasticity of BRG1 expression in response to tumor microenvironments during malignant progression. This dynamic and reciprocal cross-talk between colorectal cancer cells and M2 macrophages provides a new opportunity for the treatment of metastatic colorectal cancer. Significance: These findings report a functional role for miRNA-containing exosomes derived from M2 macrophages in regulating migration and invasion of colorectal cancer cells.

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Section: Discussionsupporting

confidence: 89%

M2 Macrophage-Derived Exosomes Promote Cell Migration and Invasion in Colon Cancer

et al. 2019

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“…Several identified miRNAs and their target genes contribute to tissue fibrosis, which is one of histopathologic characteristics associated with DFUs . Up‐regulation of miR‐21‐5p has been observed in dermal compartment of chronic wounds and skin diseases, including in primary dermal fibroblasts derived from VLUs and systemic sclerosis, as well as in normal dermal fibroblasts that undergo replicative and stress‐induced senescence stage . Consistent with these observations, we found a significant increase of miR‐21‐5p expression in DFUF, and corresponding down‐regulation of its five target genes, namely integrin associated protein (CD47), S100 calcium binding protein A10 (S100A10), protein sprouty homolog 1 (SPRY1), signal transducer and activator of transcription 3 (STAT3), reversion‐inducing‐cysteine‐rich protein with kazal motifs (RECK).…”

Section: Discussionsupporting

confidence: 85%

Integrative analysis of miRNA and mRNA paired expression profiling of primary fibroblast derived from diabetic foot ulcers reveals multiple impaired cellular functions

Liang

Stone

Stojadinović

et al. 2016

Wound Repair Regeneration

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Diabetic foot ulcers (DFUs) are one of the major complications of diabetes. Its molecular pathology remains poorly understood, impeding the development of effective treatments. Although it has been established that multiple cell types, including fibroblasts, keratinocytes, macrophages and endothelial cells, all contribute to inhibition of healing, less is known regarding contributions of individual cell type. Thus, we generated primary fibroblasts from non-healing DFUs and evaluated their cellular and molecular properties in comparison to non-diabetic foot fibroblasts (NFFs). Specifically, we analyzed both micro-RNA and mRNA expression profiles of primary DFU fibroblasts. Paired genomic analyses identified a total of 331 reciprocal miRNA-mRNA pairs including 21 miRNAs (FC>2.0) along with 239 predicted target genes (FC>1.5) that are significantly and differentially expressed. Of these, we focused on three miRNAs (miR-21-5p, miR-34a-5p, miR-145-5p) that were induced in DFU fibroblasts as most differentially regulated. The involvement of these microRNAs in wound healing was investigated by testing the expression of their downstream targets as well as by quantifying cellular behaviors in prospectively collected and generated cell lines from 15 patients (7 DFUF and 8 NFF samples). We found large number of downstream targets of miR-21-5p, miR-34a-5p, miR-145-5p to be coordinately regulated in mRNA profiles, which was confirmed by qPCR. Pathway analysis on paired miRNA-mRNA profiles predicted inhibition of cell movement and cell proliferation, as well as activation of cell differentiation and senescence in DFU fibroblasts, which was confirmed by cellular assays. We concluded that induction of miR-21-5p, miR-34a-5p, miR-145-5p in DFU dermal fibroblasts plays an important role in impairing multiple cellular functions, thus contributing to overall inhibition of healing in DFUs.

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“…For example, increased miR‐146a expression in aged macrophages limits cellular responses to LPS (Jiang et al, ). Elevated miR‐21 can also induce senescence and reduce angiogenic potential in endothelial cells (Dellago et al, ) as well as impair T‐cell activation (Kim et al, ). Changes in miR‐223 and let‐7a expression have also been shown to affect a number of myeloid cell processes including the response to cell activation (Cho, Song, Oh, & Lee, ; M'Baya‐Moutoula et al, ).…”

Section: Discussionmentioning

confidence: 99%

Cellular senescence contributes to age‐dependent changes in circulating extracellular vesicle cargo and function

et al. 2020

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Extracellular vesicles (EVs) have emerged as important regulators of inter‐cellular and inter‐organ communication, in part via the transfer of their cargo to recipient cells. Although circulating EVs have been previously studied as biomarkers of aging, how circulating EVs change with age and the underlying mechanisms that contribute to these changes are poorly understood. Here, we demonstrate that aging has a profound effect on the circulating EV pool, as evidenced by changes in concentration, size, and cargo. Aging also alters particle function; treatment of cells with EV fractions isolated from old plasma reduces macrophage responses to lipopolysaccharide, increases phagocytosis, and reduces endothelial cell responses to vascular endothelial growth factor compared to cells treated with young EV fractions. Depletion studies indicate that CD63+ particles mediate these effects. Treatment of macrophages with EV‐like particles revealed that old particles increased the expression of EV miRNAs in recipient cells. Transfection of cells with microRNA mimics recapitulated some of the effects seen with old EV‐like particles. Investigation into the underlying mechanisms using bone marrow transplant studies revealed circulating cell age does not substantially affect the expression of aging‐associated circulating EV miRNAs in old mice. Instead, we show that cellular senescence contributes to changes in particle cargo and function. Notably, senolytic treatment of old mice shifted plasma particle cargo and function toward that of a younger phenotype. Collectively, these results demonstrate that senescent cells contribute to changes in plasma EVs with age and suggest a new mechanism by which senescent cells can affect cellular functions throughout the body.

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High levels of onco-miR-21 contribute to the senescence-induced growth arrest in normal human cells and its knock-down increases the replicative lifespan

Cited by 8 publications

References 38 publications

M2 Macrophage-Derived Exosomes Promote Cell Migration and Invasion in Colon Cancer

M2 Macrophage-Derived Exosomes Promote Cell Migration and Invasion in Colon Cancer

Integrative analysis of miRNA and mRNA paired expression profiling of primary fibroblast derived from diabetic foot ulcers reveals multiple impaired cellular functions

Cellular senescence contributes to age‐dependent changes in circulating extracellular vesicle cargo and function

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