Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

Biswas, Surajit; Roy, Sashwati; Banerjee, Jaideep; Hussain, Syed-Rehan A.; Khanna, Savita; Meenakshisundaram, Guruguhan; Kuppusamy, Periannan; Friedman, Avner; Sen, Chandan K.

doi:10.1073/pnas.1001653107

Cited by 244 publications

(205 citation statements)

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“…25 Similarly, miRNA-494 was recently found to be localized to mitochondria, where it may target genes involved in ATP synthesis-coupled electron transport. 26 Of note, miR-210 also suppresses cell-cycle progression by targeting E2F3 27 and fibroblast growth factor receptor-like-1 (FGFRL1). 28 miR-376a* was reported to repress phosphoribosyl pyrophosphate synthetase-1 (PRPS1) involved in DNA/ RNA synthesis as well as threonine and tyrosine kinase (TTK) essential for mitosis checkpoint.…”

Section: Discussionmentioning

confidence: 99%

A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts

et al. 2011

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Here we show that replicative senescence in normal human diploid IMR90 fibroblasts is accompanied by altered expression of a set of microRNAs (miRNAs) (senescence-associated miRNAs), with 14 and 10 miRNAs being either up or downregulated (42-fold), respectively, in senescent with respect to young cells. The expression of most of these miRNAs was also deregulated upon senescence induced by DNA damage (etoposide) or mild oxidative stress (diethylmaleate). Four downregulated miRNAs were part of miRNA family-17, recently associated to human cell and tissue aging. Moreover, eight upregulated and six downregulated miRNAs mapped in specific chromosomal clusters, suggesting common transcriptional regulation. Upon adoptive overexpression, seven upregulated miRNAs induced the formation of senescence-associated heterochromatin foci and senescence-associated b-galactosidase staining (Po0.05), which was accompanied, in the case of five of them, by reduced cell proliferation. Finally, miR-210, miR-376a*, miR-486-5p, miR-494, and miR-542-5p induced double-strand DNA breaks and reactive oxygen species accumulation in transfected cells. In conclusion, we have identified a set of human miRNAs induced during replicative and chemically induced senescence that are able to foster the senescent phenotype by prompting DNA damage. Replicative or cellular senescence, a state of irreversible arrest of cell division, was first described in cultures of human fibroblasts. 1 Since then, replicative senescence has been described in various mammalian cells. 2 The mechanisms underlying senescence include telomere shortening, upregulation of the CDKN1A (p21WAF1) and CDKN2A (p16INK4a and p14ARF) loci, and accumulation of DNA damage. 3 Telomeres become progressively shorter at every round of cell division and this leads to critically short telomere length sensed as double-strand DNA breaks. 4 DNA damage and DNA-damage response (DDR) could be common events to cellular senescence programs initiated by telomere dysfunction and aberrant oncogene activation. 5 Senescent cells are marked by lack of DNA replication; expression of senescence-associated b-galactosidase (SA-b-gal); accumulation of discrete nuclear foci that are termed senescence-associated heterochromatin foci (SAHFs); and senescence-associated DNA-damage foci (SDFs). SAHFs are detected by preferential binding of DNA dyes, such as 4 0 ,6-diamidino-2-phenylindole (DAPI), and the presence of certain heterochromatin-associated histone modifications (trimethyl-Lys9 Histone H3). SDFs are nuclear foci containing proteins that are associated to DNA damage (Ser139-phosphorylated histone H2AX -g-H2AX-and p53-binding protein-1-53BP1). 6 Senescent cells show striking changes in gene expression, including upregulation of cell-cycle inhibitors (p21WAF1 and p16INK4a) and secreted proteins involved in microenvironment remodeling (IL-6), 7 and downregulation of genes that facilitate cell-cycle progression (c-FOS, cyclin-A, cyclin-B, PCNA) 8 or that are involved in cell-cycle execution (FOXM1, UBE2C, TYMS). ...

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Section: Discussionmentioning

confidence: 99%

A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts

et al. 2011

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“…Cell Proliferation-Transfected cells were seeded in 96-well plate, and cell proliferation was determined by the CyQUANT cell proliferation assays (Invitrogen) as described previously (19).…”

Section: Methodsmentioning

confidence: 99%

The MicroRNA miR-199a-5p Down-regulation Switches on Wound Angiogenesis by Derepressing the v-ets Erythroblastosis Virus E26 Oncogene Homolog 1-Matrix Metalloproteinase-1 Pathway

Chan

Roy

Huang

et al. 2012

Journal of Biological Chemistry

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Background:The role of miR-199a-5p in angiogenesis remains unclear. Results: miR-199a-5p exerts angiostatic effects by targeting Ets-1-MMP1 pathway and is down-regulated in skin wound healing. Conclusion: Down-regulation of miR-199a-5p switches on wound angiogenesis through derepressing of Ets-1-MMP1 pathway. Significance: This investigation provides novel mechanistic insight explaining miR-dependent regulation of wound angiogenesis and the foundation of developing therapeutic intervention in treating chronic nonhealing wounds.

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“…There is accumulating evidence that dysregulation of the expression of particular miRNAs occurs following exposure to hypoxia. These miRNAs have been implicated in a broad range of biological processes including cell proliferation, apoptosis, differentiation, metabolism, migration and invasion (17,18). A previous study confirmed that miR-210 is induced by hypoxia in hepatocellular carcinoma cells and may promote cancer cell metastasis (19).…”

Section: Discussionmentioning

confidence: 81%

Hypoxia promotes C-X-C chemokine receptor type 4 expression through microRNA-150 in pancreatic cancer cells

et al. 2015

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Abstract. Hypoxia promotes pancreatic cancer progression by triggering cancer cell invasion. However, the mechanism underlying this process remains unclear, hindering the development of effective therapies. The present study aimed to delineate the molecular mechanisms underlying the prometastatic effect of hypoxia in pancreatic cancer cells. The expression of microRNA-150 (miRNA-150) was detected using reverse transcription-quantitative polymerase chain reaction in pancreatic cancer samples and in the hypoxia-induced CaPan2 human pancreatic cancer cell line. The target gene was identified using bioinformatics and a luciferase reporter assay. Inhibition of the expression of C-X-C chemokine receptor type 4 (CXCR4) by miRNA-150 was confirmed using transfection with miRNA-150 mimics. The prometastatic effect of hypoxia was detected using migration assays. The expression of miRNA-150 was shown to be downregulated in pancreatic cancer samples compared with that in normal pancreatic tissue samples. Furthermore, its expression was reduced in hypoxia-induced CaPan2 cells, compared with that in control cells. Bioinformatics and the results of the luciferase reporter assay, demonstrated that miRNA-150 inhibited the expression of CXCR4 by directly targeting the 3' untranslated region of CXCR4 mRNA. The results of the migration assay showed that hypoxia promotes cell migration and invasion. However, this prometastatic effect was reversed by transfection with miRNA-150 mimics. The present results suggest that hypoxia promotes pancreatic cancer migration by downregulating miRNA-150. IntroductionPancreatic cancer (PC) is among the most lethal malignancies, with a high incidence and rate of metastasis (1). At the time of diagnosis, the majority of patients are at an advanced stage of disease, with multi-organ metastasis, which indicates a poor prognosis for digestive system tumors (2). It is challenging to diagnose PC at an early stage, which results in a low 5-year survival rate; only 4% of patients diagnosed with pancreatic cancer survive after 5 years in China (3). Therefore, the identification of novel gene targets, which are differentially expressed in PC and functionally involved in the development of malignant phenotypes, is required in order to enable early diagnosis and the development of effective therapeutic strategies.Hypoxia is an important characteristic of solid tumors. As a tumor increases in size, it quickly outgrows its blood supply, leaving regions of the tumor, in which the oxygen concentration is significantly lower than that in normal tissues. In order to support tumor growth and proliferation within hypoxic environments, the expression of a number of genes is altered, and changes in metabolism also occur (4). Recently, a novel class of endogenous small non-coding regulatory RNAs, termed microRNAs (miRNAs), has received increasing attention. These small molecules exert their regulatory effects by base pairing with partially complementary messenger RNAs (mRNAs). They act via one of two mechanisms: Degradatio...

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Hypoxia inducible microRNA 210 attenuates keratinocyte proliferation and impairs closure in a murine model of ischemic wounds

Cited by 244 publications

References 41 publications

A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts

A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts

The MicroRNA miR-199a-5p Down-regulation Switches on Wound Angiogenesis by Derepressing the v-ets Erythroblastosis Virus E26 Oncogene Homolog 1-Matrix Metalloproteinase-1 Pathway

Hypoxia promotes C-X-C chemokine receptor type 4 expression through microRNA-150 in pancreatic cancer cells

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