Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5
Exosomal miR-196a derived from cancer-associated fibroblasts confers cisplatin resistance in head and neck cancer through targeting CDKN1B and ING5
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源自癌症相关成纤维细胞的外泌体 miR-196a 通过靶向 CDKN1B 和 ING5 赋予头颈癌顺铂耐药性
DOI：
10.1186/s13059-018-1604-0
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发表时间：
2019-01-14
期刊：
影响因子：
12.3
通讯作者：
Zhang, Jianjun
中科院分区：
文献类型：
--
作者：
Qin, Xing;Guo, Haiyan;Zhang, Jianjun
顺铂耐药是晚期头颈癌（HNC）的主要挑战。了解潜在的机制和制定有效的策略对抗顺铂耐药是迫切需要在临床。然而，肿瘤基质如何调节HNC生长和化疗耐药尚不清楚。结果我们发现，癌症相关成纤维细胞（CAFs）本质上对顺铂具有耐药性，并通过将功能性miR-196a从CAFs通过外泌体传递到肿瘤细胞中，在调节HNC细胞存活和增殖中发挥积极作用。然后外泌体miR-196a结合新的靶点CDKN1B和ING5，赋予HNC细胞顺铂耐药性。CAFs外泌体或外泌体miR-196a缺失功能恢复HNC顺铂敏感性。重要的是，我们发现miR-196a包装到cafd衍生的外泌体中可能是由异质核核糖核蛋白A1 （hnRNPA1）介导的。此外，我们还发现高水平的血浆外泌体miR-196a在临床上与较差的总生存率和化疗耐药相关。本研究发现，caf来源的外泌体miR-196a通过靶向CDKN1B和ING5，在HNC中产生顺铂耐药，这表明miR-196a可能是HNC顺铂耐药的一个有希望的预测因子和潜在的治疗靶点。
BackgroundCisplatin resistance is a major challenge for advanced head and neck cancer (HNC). Understanding the underlying mechanisms and developing effective strategies against cisplatin resistance are highly desired in the clinic. However, how tumor stroma modulates HNC growth and chemoresistance is unclear.ResultsWe show that cancer-associated fibroblasts (CAFs) are intrinsically resistant to cisplatin and have an active role in regulating HNC cell survival and proliferation by delivering functional miR-196a from CAFs to tumor cells via exosomes. Exosomal miR-196a then binds novel targets, CDKN1B and ING5, to endow HNC cells with cisplatin resistance. Exosome or exosomal miR-196a depletion from CAFs functionally restored HNC cisplatin sensitivity. Importantly, we found that miR-196a packaging into CAF-derived exosomes might be mediated by heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Moreover, we also found that high levels of plasma exosomal miR-196a are clinically correlated with poor overall survival and chemoresistance.ConclusionsThe present study finds that CAF-derived exosomal miR-196a confers cisplatin resistance in HNC by targeting CDKN1B and ING5, indicating miR-196a may serve as a promising predictor of and potential therapeutic target for cisplatin resistance in HNC.