Reprogramming carcinoma associated fibroblasts by AC1MMYR2 impedes tumor metastasis and improves chemotherapy efficacy
Reprogramming carcinoma associated fibroblasts by AC1MMYR2 impedes tumor metastasis and improves chemotherapy efficacy
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AC1MMYR2对癌相关成纤维细胞进行重编程可阻止肿瘤转移并提高化疗效果
DOI：
10.1016/j.canlet.2016.02.003
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发表时间：
2016-04-28
期刊：
影响因子：
9.7
通讯作者：
Kang, Chun-sheng
中科院分区：
文献类型：
--
作者：
Ren, Yu;Zhou, Xuan;Kang, Chun-sheng
癌相关成纤维细胞（CAFs）产生一个营养丰富的微环境来促进肿瘤的进展和转移。活性氧（ROS）水平和炎症途径协同转化CAFs。因此，阐明介导CAFs活性的机制可能会发现新的治疗方法。据报道，异常miR-21表达参与了常驻成纤维细胞向CAFs的转化，但驱动转化的因素尚不清楚。在这里，我们报道了miR-21的高表达与乳腺癌的淋巴结转移密切相关，并且CAFs的转移促进作用需要激活miR-21/NF-kappa B。AC1MMYR2是一种miR-21的小分子抑制剂，通过直接靶向VHL来减弱NF-kappa B的活性，从而阻断NF-kappa B和β -连环蛋白的共沉淀和核易位。紫杉醇不能抑制CAFs刺激的癌细胞的侵袭行为，而AC1MMYR2加紫杉醇能显著抑制肿瘤的迁移和侵袭能力。在联合治疗中也检测到F-actin的重塑和去极化，β -catenin和vimentin水平降低，E-cadherin水平升高。此外，观察到fap - α和α - sma水平降低，表明AC1MMYR2能够通过NF-kappa B/miR-21/VHL轴重编程CAFs。引人注目的是，在联合治疗的小鼠中观察到肿瘤生长和肺转移的显著减少。综上所述，我们的研究结果确定了miR-21是乳腺癌通过肿瘤环境转移的关键介质。AC1MMYR2可能会转化为临床，并发展成为一种更个性化和有效的新辅助治疗方法，以减少转移和改善化疗反应。2016爱思唯尔爱尔兰有限公司版权所有。
Carcinoma associated fibroblasts (CAFs) produce a nutrient-rich microenvironment to fuel tumor progression and metastasis. Reactive oxygen species (ROS) levels and the inflammation pathway cooperate to transform CAFs. Therefore, elucidating the mechanism mediating the activity of CAFs might identify novel therapies. Abnormal miR-21 expression was reported to be involved in the conversion of resident fibroblasts to CAFs, yet the factor that drives transformation was poorly understood. Here, we reported that high miR-21 expression was strongly associated with lymph node metastasis in breast cancer, and the activation of the miR-21/NF-kappa B was required for the metastatic promoting effect of CAFs. AC1MMYR2, a small molecule inhibitor of miR-21, attenuated NF-kappa B activity by directly targeting VHL, thereby blocking the co-precipitation of NF-kappa B and beta-catenin and nuclear translocation. Taxol failed to constrain the aggressive behavior of cancer cells stimulated by CAFs, whereas AC1MMYR2 plus taxol significantly suppressed tumor migration and invasion ability. Remodeling and depolarization of F-actin, decreased levels of beta-catenin and vimentin, and increased E-cadherin were also detected in the combination therapy. Furthermore, reduced levels of FAP-alpha and alpha-SMA were observed, suggesting that AC1MMYR2 was competent to reprogram CAFs via the NF-kappa B/miR-21/VHL axis. Strikingly, a significant reduction of tumor growth and lung metastasis was observed in the combination treated mice. Taken together, our findings identified miR-21 as a critical mediator of metastasis in breast cancer through the tumor environment. AC1MMYR2 may be translated into the clinic and developed as a more personalized and effective neoadjuvant treatment for patients to reduce metastasis and improve the chemotherapy response. (C) 2016 Elsevier Ireland Ltd. All rights reserved.