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Pancreatic cancer cell-derived exosomal microRNA-27a promotes angiogenesis of human microvascular endothelial cells in pancreatic cancer via BTG2.

ABSTRACT: Pancreatic cancer (PC) remains a primary cause of cancer-related deaths worldwide. Existing literature has highlighted the oncogenic role of microRNA-27a (miR-27a) in multiple cancers. Hence, the current study aimed to clarify the potential therapeutic role of PC cell-derived exosomal miR-27a in human microvascular endothelial cell (HMVEC) angiogenesis in PC. Initially, differentially expressed genes (DEGs) and miRs related to PC were identified by microarray analysis. Microarray analysis provided data predicting the interaction between miR-27a and BTG2 in PC, which was further verified by the elevation or depletion of miR-27a. Next, the expression of miR-27a and BTG2 in the PC tissues was quantified. HMVECs were exposed to exosomes derived from PC cell line PANC-1 to investigate the effects associated with PC cell-derived exosomes carrying miR-27a on HMVEC proliferation, invasion and angiogenesis. Finally, the effect of miR-27a on tumorigenesis and microvessel density (MVD) was analysed after xenograft tumour inoculation in nude mice. Our results revealed that miR-27a was highly expressed, while BTG2 was poorly expressed in both PC tissues and cell lines. miR-27a targeted BTG2. Moreover, miR-27a silencing inhibited PC cell proliferation and invasion, and promoted apoptosis through the elevation of BTG2. The in vitro assays revealed that PC cell-derived exosomes carrying miR-27a stimulated HMVEC proliferation, invasion and angiogenesis, while this effect was reversed in the HMVECs cultured with medium containing GW4869-treated PANC-1 cells. Furthermore, in vivo experiment revealed that miR-27a knockdown suppressed tumorigenesis and MVD. Taken together, cell-derived exosomes carrying miR-27a promotes HMVEC angiogenesis via BTG2 in PC.

SUBMITTER: Shang D

PROVIDER: S-EPMC6933412 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Pancreatic cancer cell-derived exosomal microRNA-27a promotes angiogenesis of human microvascular endothelial cells in pancreatic cancer via BTG2.

Shang Dan D Xie Chao C Hu Jin J Tan Jinru J Yuan Yufeng Y Liu Zhisu Z Yang Zhiyong Z

Journal of cellular and molecular medicine 20191113 1

Pancreatic cancer (PC) remains a primary cause of cancer-related deaths worldwide. Existing literature has highlighted the oncogenic role of microRNA-27a (miR-27a) in multiple cancers. Hence, the current study aimed to clarify the potential therapeutic role of PC cell-derived exosomal miR-27a in human microvascular endothelial cell (HMVEC) angiogenesis in PC. Initially, differentially expressed genes (DEGs) and miRs related to PC were identified by microarray analysis. Microarray analysis provid ...[more]

PMID: 31724333

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Project description:Background: By providing oxygen, nutrients and metastatic conduits, tumour angiogenesis is essential for cancer metastasis. Cancer cell-secreted microRNAs can be packaged into exosomes and are implicated in different aspects of tumour angiogenesis. However, the underlying mechanisms are incompletely understood. Methods: The GEPIA database and in situ hybridization assay were used to analyse expression of miR-205 in ovarian tissues. Immunohistochemistry was performed to examine the relationship between miR-205 and microvessel density. Expression of circulating miR-205 was evaluated by RT-PCR and GEO database analysis. Co-culture and exosome labelling experiments were performed to assess exosomal miR-205 transfer from ovarian cancer (OC) cells to endothelial cells ECs. Exosome uptake assays were employed to define the cellular pathways associated with the endocytic uptake of exosomal miR-205. The role of exosomal miR-205 in angiogenesis was further investigated in vivo and in vitro. Western blotting and rescue experiments were applied to detect regulation of the PTEN-AKT pathway by exosomal miR-205 in ECs. Results: miR-205 was up-regulated in OC tissues, and high expression of miR-205 was associated with metastatic progression in OC patients. Moreover, miR-205 was highly enriched in cancer-adjacent ECs, and up-regulation of miR-205 correlated positively with high microvessel density in OC patients. Importantly, miR-205 was markedly enriched in the serum of OC patients, and a high level of miR-205 in circulating exosomes was associated with OC metastasis. In addition, OC-derived miR-205 was secreted into the extracellular space and efficiently transferred to adjacent ECs in an exosome-dependent manner, and the lipid raft-associated pathway plays an important role in regulating uptake of exosomal miR-205. Exosomal miR-205 from OC cells significantly promoted in vitro angiogenesis and accelerated angiogenesis and tumour growth in a mouse model. Furthermore, we found that exosomal miR-205 induces angiogenesis via the PTEN-AKT pathway. Conclusion: These findings demonstrate an exosome-dependent mechanism by which miR-205 derived from cancer cells regulates tumour angiogenesis and implicate exosomal miR-205 as a potential therapeutic target for OC.

Project description:Background:Hypoxia following ischemic stroke is a common cause of brain insults. Mounting evidence suggests that long non-coding RNAs (lncRNAs) play a vital role in regulating certain physiological and pathological processes including ischemic stroke. For the first time, the present study investigated the effects and mechanism of LncRNA MACC1-AS1 on hypoxia-induced human brain microvascular endothelial cells (HBMECs). Methods:LncRNA MACC1-AS1 levels in HBMECs were detected via reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT), were detected using their respective kits. Flow cytometry and clone formation assay were performed to evaluate the effects of lncRNA MACC1-AS1 on cell apoptosis and cell proliferation respectively. Angiogenesis capacity was evaluated via tube formation assay. Transwell migration assay was performed for assessment of cell migration, Western blot assay was performed for measurement of Twist1 and VE-cadherin level, and permeability assay was performed for evaluation of the cell barrier function. The target gene was predicted via bioinformatics online tool and validated through luciferase reporter assay and RNA pull-down assay. Results:LncRNA MACC1-AS1 was downregulated in hypoxia-induced HBMECs. Overexpression of LncRNA MACC1-AS1 reduced cell apoptosis and oxidative stress, while promoting cell proliferation, migration, and angiogenesis. Moreover, LncRNA MACC1-AS1 overexpression reduced cell permeability and elevated VE-cadherin level, which contributed to maintaining cell barrier function. TWIST1 was validated as the target of miR-6867-5p which was further targeted by lncRNA MACC1-AS1. Thus, LncRNA MACC1-AS1 functions in hypoxia-induced HBMECs by regulating miR-6867-5p/TWIST1. Conclusions:In this study, we found that LncRNA MACC1-AS1 exerted a protective role in hypoxia-induced HBMECs via regulating miR-6867-5p/TWIST1, indicating a new therapeutic strategy for future ischemic stroke therapy.

Dataset Information

Pancreatic cancer cell-derived exosomal microRNA-27a promotes angiogenesis of human microvascular endothelial cells in pancreatic cancer via BTG2.

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Pancreatic cancer cell-derived exosomal microRNA-27a promotes angiogenesis of human microvascular endothelial cells in pancreatic cancer via BTG2.

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