Wang Huan, Wang Lie, Pan Haiyan, Wang Yaona, Shi Miao, Yu Hang, Wang Chaoye, Pan Xinfu, Chen Zhijun
Department of Cardiothoracic Surgery, Zhoushan Hospital, Zhejiang University, Zhoushan, China.
Department of Internal Medicine, Zhoushan Hospital, Zhejiang University, Zhoushan, China.
Front Cell Dev Biol. 2021 Mar 4;8:620603. doi: 10.3389/fcell.2020.620603. eCollection 2020.
As one of the most common and lethal cancer, lung cancer severely threatens the health of human. It has been reported that tumor-associated macrophages promote initiation, progression, as well as chemoresistance in human cancers. However, the underneath molecular mechanism that drives chemoresistance in lung cancer is yet not fully characterized. In this article, we demonstrated that M2 macrophage-derived exosomes (MDE) is the key factor to promote cisplatin-resistance in lung cancer. MDE exhibited high expression level of several miRNA including miR-3679-5p. Mechanistically, miR-3679-5p was delivered to lung cancer cells by MDE, downregulating the expression of a known E3 ligase, NEDD4L, which has been identified as a key regulator controlling the stability of c-Myc. Such decreased NEDD4L expression level resulted in the stabilization of c-Myc and elevated glycolysis. The enhanced glycolysis drives the chemoresistance in lung cancer. Taken together, our findings not only show that M2 macrophage induce chemoresistance in lung cancer through MDE mediated miR-3679-5R/NEDD4L/c-Myc signaling cascade, but also shed the light on the mechanism of the cross-talk between M2 macrophage and lung cancers. By pinpointing a potential novel survival signaling pathway, our data could provide a new potential therapeutic target for lung cancer treatment and management.
作为最常见且致命的癌症之一，肺癌严重威胁人类健康。据报道，肿瘤相关巨噬细胞在人类癌症中促进肿瘤起始、进展以及化疗耐药。然而，驱动肺癌化疗耐药的潜在分子机制尚未完全明确。在本文中，我们证明M2巨噬细胞衍生的外泌体（MDE）是促进肺癌顺铂耐药的关键因素。MDE表现出包括miR-3679-5p在内的几种miRNA的高表达水平。机制上，miR-3679-5p通过MDE传递至肺癌细胞，下调已知的E3连接酶NEDD4L的表达，NEDD4L已被确定为控制c-Myc稳定性的关键调节因子。NEDD4L表达水平的降低导致c-Myc的稳定和糖酵解增加。增强的糖酵解驱动肺癌的化疗耐药。综上所述，我们的研究结果不仅表明M2巨噬细胞通过MDE介导的miR-3679-5R/NEDD4L/c-Myc信号级联在肺癌中诱导化疗耐药，还揭示了M2巨噬细胞与肺癌之间的相互作用机制。通过确定一条潜在的新的生存信号通路，我们的数据可为肺癌治疗和管理提供一个新的潜在治疗靶点。
