Anti-angiogenesis effect of Neferine via regulating autophagy and polarization of tumor-associated macrophages in high-grade serous ovarian carcinoma
Anti-angiogenesis effect of Neferine via regulating autophagy and polarization of tumor-associated macrophages in high-grade serous ovarian carcinoma
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莲心碱通过调节高级别浆液性卵巢癌肿瘤相关巨噬细胞的自噬和极化来发挥抗血管生成作用
DOI：
10.1016/j.canlet.2018.05.049
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发表时间：
2018
期刊：
影响因子：
9.7
通讯作者：
Kong Beihua
中科院分区：
文献类型：
--
作者：
Zhang Qing;Li Yinuo;Miao Chunying;Wang Yugiong;Xu Ying;Dong Ruifen;Zhang Zhiwei;Griffin Brannan B.;Yuan Cunzhong;Yan Shi;Yang Xingsheng;Liu Zhaojian;Kong Beihua
高级别浆液性卵巢癌（HGSOC）是妇科最致命的恶性肿瘤之一。目前，抗血管生成治疗是成功治疗HGSOC的最有希望的策略。本研究发现甲基莲心碱在体外和体内均能抑制卵巢癌细胞的血管生成。进一步分析表明，其对人脐静脉内皮细胞（HUVEC）增殖的抑制作用与促进细胞周期阻滞和自噬有关。细胞周期基因呈剂量依赖性降低，LC 3 II/LC 3 I（微管相关蛋白1轻链3）水平升高。利用巨噬细胞特异性标志物（CD 206和Mrc 1），我们表明甲基莲心碱在体内可抑制M2-巨噬细胞。最后，CD 206在150例HGSOC样本中被染色，其高表达预测较差的总生存期。我们目前的研究首次证明甲基莲心碱通过抑制mTOR/p70 S6 K通路诱导自噬和抑制M2-巨噬细胞极化来抑制血管生成的机制。我们的研究结果表明甲基莲心碱是一种有吸引力的试剂，在HGSOC治疗中具有很大的潜力，特别是在标准治疗耐药的病例中。
High-grade serous ovarian carcinoma (HGSOC) is one of the most lethal gynecologic malignancies. Currently, anti-angiogenesis therapy is the most promising strategy for the successful treatment of HGSOC. In this study, we found Neferine could inhibit the angiogenesis of ovarian cancer cells bothin vitroandin vivo. Further analysis revealed that its suppressive effect on human umbilical vein endothelial cell (HUVEC) proliferation correlated with promoting cell cycle arrest and autophagy. The cell cycle genes were dose-dependently reduced and the level of LC3II/LC3I (microtubule associated protein 1 light chain 3) was increased. Using a specific marker for macrophages (CD206 and Mrc1), we indicated that Neferine could inhibit M2-macrophagein vivo. Finally, CD206 was stained in 150 HGSOC samples and its high expression predicted inferior overall survival. Our current study is the first to demonstrate the anti-angiogenesis mechanism of Neferine by inducing autophagy via mTOR/p70S6K pathway inhibition and suppressing M2-macrophage polarization. Our findings suggest that Neferine is an attractive reagent with great potential in HGSOC therapy, especially in standard-therapy resistant cases.