Theranostics 2019; 9(26):8206-8220. doi:10.7150/thno.37455

Research Paper

Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis

Liuqing He1,2, Wei Zhu1,2, Quan Chen1,2, Yishu Yuan1,2, Yixuan Wang1,2, Junpu Wang1,2, Xiaoying Wu1,2✉

1. Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, P.R. China;
2. Department of Pathology, School of Basic Medical Science, Central South University, Changsha, Hunan 410013, P. R. China.

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Citation:
He L, Zhu W, Chen Q, Yuan Y, Wang Y, Wang J, Wu X. Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis. Theranostics 2019; 9(26):8206-8220. doi:10.7150/thno.37455. Available from http://www.thno.org/v09p8206.htm

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Abstract

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.

Keywords: ovarian cancer, exosomes, miR-205, angiogenesis, metastasis