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TKI-Resistant Renal Cancer Secretes Low-Level Exosomal miR-549a to Induce Vascular Permeability and Angiogenesis to Promote Tumor Metastasis.

ABSTRACT: Tyrosine kinase inhibitors (TKI)-resistant renal cancer is highly susceptible to metastasis, and enhanced vascular permeability promotes the process of metastasis. To evaluate the effect of cancer-derived exosomes on vascular endothelial cells and clarify the mechanism of metastasis in TKI-resistant renal cancer, we studied the crosstalk between clear cell renal cell carcinoma (ccRCC) cells and human umbilical vein endothelial cells (HUVECs). Exosomes from ccRCC cells enhanced the expression of vascular permeability-related proteins. Compared with sensitive strains, exosomes from resistant strains significantly enhanced vascular endothelial permeability, induced tumor angiogenesis and enhanced tumor lung metastasis in nude mice. The expression of miR-549a is lower in TKI-resistant cells and exosomes, which enhanced the expression of HIF1α in endothelial cells. In addition, TKI-resistant RCC cells reduced nuclear output of pre-miR-549a via the VEGFR2-ERK-XPO5 pathway, and reduced enrichment of mature miR-549a in cytoplasm, which in turn promoted HIF1α expression in RCC, leading to increased VEGF secretion and further activated VEGFR2 to form a feedback effect. miR-549a played an important role in the metastasis of renal cancer and might serve as a blood biomarker for ccRCC metastasis and even had the potential of becoming a new drug to inhibit TKI-resistance.

SUBMITTER: Xuan Z

PROVIDER: S-EPMC8222687 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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TKI-Resistant Renal Cancer Secretes Low-Level Exosomal miR-549a to Induce Vascular Permeability and Angiogenesis to Promote Tumor Metastasis.

Xuan Zuodong Z Chen Chen C Tang Wenbin W Ye Shaopei S Zheng Jianzhong J Zhao Yue Y Shi Zhiyuan Z Zhang Lei L Sun Huimin H Shao Chen C

Frontiers in cell and developmental biology 20210610

Tyrosine kinase inhibitors (TKI)-resistant renal cancer is highly susceptible to metastasis, and enhanced vascular permeability promotes the process of metastasis. To evaluate the effect of cancer-derived exosomes on vascular endothelial cells and clarify the mechanism of metastasis in TKI-resistant renal cancer, we studied the crosstalk between clear cell renal cell carcinoma (ccRCC) cells and human umbilical vein endothelial cells (HUVECs). Exosomes from ccRCC cells enhanced the expression of ...[more]

PMID: 34179017

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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:BackgroundMetastasis is the main cause of death in colorectal cancer (CRC). Circulating tumour cells (CTCs) are regarded as the precursor cells of metastasis. The CTCs, which underwent epithelial-mesenchymal transition (EMT), are associated with metastasis and responsible for poor prognosis. EMT cancer cells modulate endothelial permeability in the invasive front and facilitate cancer cell intravasation, resulting in CTCs-mediated distant metastasis. Exosomes derived from cancer cells are key mediators of cancer-host intercommunication. However, the mechanism by which EMT-tumour cells-derived exosomes modulate vascular permeability and promote CTCs generation has remained unclear.MethodsExosomes isolation and purification were conducted by ultra-centrifugation. Exosomal miRNA was identified by sequencing followed by quantitative PCR. In vitro co-culture assay experiments were conducted to evaluate the effect of exosomal miR-27b-3p on the permeability of blood vessel endothelium. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) and RNA immunoprecipitation (RIP) were performed to investigate the underlying mechanism by which miR-27b-3p is packaged into exosomes. A mouse model was established to determine the role of exosomal miR-27b-3p in blood vessel permeability modulation in vivo.ResultsWe found that EMT-CRC cells attenuate the blood vessel barrier by transferring miR-27b-3p to human umbilical vein endothelial cells (HUVECs) in exosomes. Mechanically, miR-27b-3p atteuated the expression of vascular endothelial cadherin (VE-Cad) and p120 at the post-transcriptional level by binding to 3'-untranslated region of VE-Cad and p120 directly. The packaging of miR-27b-3p into exosomes was induced by heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which activated by STAT3. Clinically, miR-27b-3p up-regulated in CRC tissues. Plasma exosomal miR-27b-3p was positively correlated with malignant progression and CTC count in CRC patients. Our study reveals a novel mechanism by which EMT-CRC cells promote metastasis, increasing blood vessel permeability and facilitating the generation of CTCs.ConclusionExosomal miR-27b-3p secreted by EMT-CRC cells increases blood vessel permeability and facilitates the generation of CTCs. Exosomal miR-27b-3p may become a promising biomarker for CRC metastasis.

Dataset Information

TKI-Resistant Renal Cancer Secretes Low-Level Exosomal miR-549a to Induce Vascular Permeability and Angiogenesis to Promote Tumor Metastasis.

Publications

TKI-Resistant Renal Cancer Secretes Low-Level Exosomal miR-549a to Induce Vascular Permeability and Angiogenesis to Promote Tumor Metastasis.

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