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

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.

RETRACTED: Upregulation of C Terminus of Hsc70-Interacting Protein Attenuates Apoptosis and Procoagulant Activity and Facilitates Brain Repair After Traumatic Brain Injury

“…Interestingly, our recent research proposed that PTEN inhibition promoted post-ischemic angiogenesis in vitro, and this enhancing effect might also be achieved through activation of the AKT signal cascade (Xue et al, 2018), which is consistent with a recent report. An ovarian cancer study by He et al (2019) showed that miR-205 could induce angiogenesis by silencing PTEN and subsequently activates AKT pathway, whereas restoring of PTEN expression can rescue the suppression of angiogenesis induced by the miR-205 inhibitor. Thus, the PTEN/AKT pathway may play a crucial role in the vascular repair and remodeling after TBI and cerebral ischemia.…”

WITHDRAWN: Targeting exosomal miR-488 inhibits head and neck squamous cell carcinoma growth by mediating RAB25

“…Exosome contents have been demonstrated to modulate the function of recipient cells (12). miRNAs in the circulating exosomes can assert cancer diagnosis due to that they facilitate cancer progression by regulating the biological behaviors of proteins (29).…”

“…Tumor-derived exosomes are now believed to promote tumor progression by inducing cell migration and activating the proliferative and angiogenic pathways. Prior studies on tumor-derived exosomes were reported in several malignancies, such as ovarian cancer and prostate cancer, and were proven to accelerate tumor metastasis (12,13).…”

Exosomal miRNAs in tumor microenvironment

“…Exosomal miR-619-5p inhibits the expression of RCAN1.4, promotes angiogenesis, and facilitates the growth and metastasis of cancer cells [128]. Recent studies have shown that circulating exosomal miR-205 expression is elevated in OC patients and is related to microvessel density, and exosomal miR-205 induces angiogenesis via the PTEN-AKT pathway, and promotes tumor cell proliferation in vitro [129]. Changes in the vascular microenvironment are not only in the number of blood vessels, but also in vascular permeability, adhesion, and ability to form a ring.…”