Ubiquitous Release of Exosomal Tumor Suppressor miR-6126 from Ovarian Cancer Cells.
Ubiquitous Release of Exosomal Tumor Suppressor miR-6126 from Ovarian Cancer Cells.
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DOI：
10.1158/0008-5472.can-16-0714
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发表时间：
2016-12-15
期刊：
影响因子：
11.2
通讯作者：
Lopez-Berestein G
中科院分区：
文献类型：
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作者：
Kanlikilicer P;Rashed MH;Bayraktar R;Mitra R;Ivan C;Aslan B;Zhang X;Filant J;Silva AM;Rodriguez-Aguayo C;Bayraktar E;Pichler M;Ozpolat B;Calin GA;Sood AK;Lopez-Berestein G
癌细胞通过基因表达重编程积极促进其致瘤行为。将特定的mirna装入腔内囊泡并将其作为外泌体释放到肿瘤微环境中是重编程的一种机制，其调控仍有待阐明。在这里，我们报告了miR-6126通过外泌体从化疗敏感和化疗耐药的卵巢癌细胞中大量释放。与卵巢癌患者样本相比，miR-6126在健康卵巢组织中被证实过表达，并与高级别浆液性卵巢癌患者更好的总生存率相关。miR-6126通过直接靶向整合素β1作为肿瘤抑制因子，整合素β1是癌细胞转移的关键调节因子。miR-6126模拟癌细胞处理导致miR-6126增加，外泌体中整合素β1 mRNA水平降低。功能分析显示，用miR-6126模拟物处理内皮细胞可显著降低卵巢癌细胞的试管形成以及体外侵袭和迁移能力。在原位卵巢癌小鼠模型中施用miR-6126模拟物可引起肿瘤生长、增殖细胞和微血管密度的相对降低。miR-6126抑制通过导致卵巢癌细胞释放更多外泌体来促进致癌行为。我们的研究结果为外泌体mirna介导的肿瘤进展的作用提供了新的见解，并提出了一种新的治疗方法来破坏肿瘤的致癌表型。
Cancer cells actively promote their tumorigenic behavior by reprogramming gene expression. Loading intraluminal vesicles with specific miRNAs and releasing them into the tumor microenvironment 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 to ovarian cancer patient samples and correlated with better overall survival in high-grade serous ovarian cancer patients. miR-6126 acted as a tumor suppressor by directly targeting integrin β1, a key regulator of cancer cell metastasis. miR-6126 mimic treatment of cancer cells resulted in increased miR-6126 and decreased integrin β1 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.