Dataset Information

MiR-497?195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1? activity.

ABSTRACT: A specific bone vessel subtype, strongly positive for CD31 and endomucin (CD31^hiEmcn^hi), is identified as coupling angiogenesis and osteogenesis. The abundance of type CD31^hiEmcn^hi vessels decrease during ageing. Here we show that expression of the miR-497?195 cluster is high in CD31^hiEmcn^hi endothelium but gradually decreases during ageing. Mice with depletion of miR-497?195 in endothelial cells show fewer CD31^hiEmcn^hi vessels and lower bone mass. Conversely, transgenic overexpression of miR-497?195 in murine endothelium alleviates age-related reduction of type CD31^hiEmcn^hi vessels and bone loss. miR-497?195 cluster maintains the endothelial Notch activity and HIF-1? stability via targeting F-box and WD-40 domain protein (Fbxw7) and Prolyl 4-hydroxylase possessing a transmembrane domain (P4HTM) respectively. Notably, endothelialium-specific activation of miR-195 by intravenous injection of aptamer-agomiR-195 stimulates CD31^hiEmcn^hi vessel and bone formation in aged mice. Together, our study indicates that miR-497?195 regulates angiogenesis coupled with osteogenesis and may represent a potential therapeutic target for age-related osteoporosis.

SUBMITTER: Yang M

PROVIDER: S-EPMC5504303 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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MiR-497∼195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity.

Yang Mi M Li Chang-Jun CJ Sun Xi X Guo Qi Q Xiao Ye Y Su Tian T Tu Man-Li ML Peng Hui H Lu Qiong Q Liu Qing Q He Hong-Bo HB Jiang Tie-Jian TJ Lei Min-Xiang MX Wan Mei M Cao Xu X Luo Xiang-Hang XH

Nature communications 20170707

A specific bone vessel subtype, strongly positive for CD31 and endomucin (CD31hiEmcnhi), is identified as coupling angiogenesis and osteogenesis. The abundance of type CD31hiEmcnhi vessels decrease during ageing. Here we show that expression of the miR-497∼195 cluster is high in CD31hiEmcnhi endothelium but gradually decreases during ageing. Mice with depletion of miR-497∼195 in endothelial cells show fewer CD31hiEmcn<s ...[more]

PMID: 28685750

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Project description:Current genome-wide microRNA (miRNA) expression signature analysis using deep sequencing technologies can drive the discovery of novel cancer pathways regulated by oncogenic and/or tumor suppressive miRNAs. We determined the genome-wide miRNA expression signature in bladder cancer (BC) by deep sequencing technology. A total of ten small RNA libraries were sequenced (five BCs and five samples of histologically normal bladder epithelia (NBE)), and 13,190,619 to 18,559,060 clean small RNA reads were obtained. A total of 933 known miRNAs and 17 new miRNA candidates were detected in this analysis. Among the known miRNAs, a total of 60 miRNAs were significantly downregulated in BC compared with NBE. We also found that several miRNAs, such as miR-1/133a, miR-206/133b, let-7c/miR-99a, miR-143/145 and miR-195/497, were located close together at five distinct loci and constituted clustered miRNAs. Among these clustered miRNAs, we focused on the miR-195/497 cluster because this clustered miRNA had not been analyzed in BC. Transfection of mature miR-195 or miR-497 in two BC cell lines (BOY and T24) significantly inhibited cancer cell proliferation, migration and invasion, suggesting that the miR-195/497 cluster functioned as tumor suppressors in BC. Regarding the genes targeted by the miR-195/497 cluster, the TargetScan algorithm showed that 6,730 genes were putative miR-195/497 targets, and 113 significantly enriched signaling pathways were identified in this analysis. The "Pathways in cancer" category was the most enriched, involving 104 candidate target genes. Gene expression data revealed that 27 of 104 candidate target genes were actually upregulated in BC clinical specimens. Luciferase reporter assays and Western blotting demonstrated that BIRC5 and WNT7A were directly targeted by miR-195/497. In conclusion, aberrant expression of clustered miRNAs was identified by deep sequencing, and downregulation of miR-195/497 contributed to BC progression and metastasis. Tumor suppressive miRNA-mediated cancer pathways provide new insights into the potential mechanisms of BC oncogenesis.

Dataset Information

MiR-497?195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1? activity.

Publications

MiR-497∼195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity.

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