Ubiquitous Release of Exosomal Tumor Suppressor miR-6126 from Ovarian Cancer Cells

作者：Kanlikilicer Pinar; Rashed Mohammed H; Bayraktar Recep; Mitra Rahul; Ivan Cristina; Aslan Burcu; Zhang Xinna; Filant Justyna; Silva Andreia M; Rodriguez Aguayo Cristian; Bayraktar Emine; Pichler Martin; Ozpolat Bulent; Calin George A; Sood Anil K; Lopez Berestein Gabriel

来源：Cancer Research, 2016, 76(24): 7194-7207.

DOI：10.1158/0008-5472.CAN-16-0714

Cancer cells actively promote their tumorigenic behavior by reprogramming gene expression. Loading intraluminal vesicles with specific miRNAs and releasing them into the tumor micro-environment as exosomes is one mechanism of reprogramming whose regulation remains to be elucidated. Here, we report that miR-6126 is ubiquitously released in high abundance from both chemosensitive and chemoresistant ovarian cancer cells via exosomes. Overexpression of miR-6126 was confirmed in healthy ovarian tissue compared with ovarian cancer patient samples and correlated with better overall survival in patients with high-grade serous ovarian cancer. miR-6126 acted as a tumor suppressor by directly targeting integrin-beta 1, a key regulator of cancer cell metastasis. miR-6126 mimic treatment of cancer cells resulted in increased miR-6126 and decreased integrin-beta 1 mRNA levels in the exosome. Functional analysis showed that treatment of endothelial cells with miR-6126 mimic significantly reduced tube formation as well as invasion and migration capacities of ovarian cancer cells in vitro. Administration of miR-6126 mimic in an orthotopic mouse model of ovarian cancer elicited a relative reduction in tumor growth, proliferating cells, and microvessel density. miR-6126 inhibition promoted oncogenic behavior by leading ovarian cancer cells to release more exosomes. Our findings provide new insights into the role of exosomal miRNA-mediated tumor progression and suggest a new therapeutic approach to disrupt oncogenic phenotypes in tumors.

• 出版日期2016-12-15