Connexin 43 upregulation by dioscin inhibits melanoma progression via suppressing malignancy and inducing M1 polarization
Connexin 43 upregulation by dioscin inhibits melanoma progression via suppressing malignancy and inducing M1 polarization
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DOI：
10.1002/ijc.30872
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发表时间：
2017-10-15
影响因子：
6.4
通讯作者：
Lu, Linlin
中科院分区：
文献类型：
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作者：
Kou, Yu;Ji, Liyan;Lu, Linlin
缝隙连接蛋白43（Cx43）是肿瘤微环境中重要的缝隙连接蛋白，具有抑瘤作用，是黑色素瘤化疗的新靶点。薯蓣皂苷是一种植物甾体皂苷，具有抗肿瘤作用，但其作用机制尚不清楚。通过WB、FACS和免疫荧光方法，我们发现薯蓣皂苷通过维甲酸信号通路显著激活了Cx43的转录和翻译，同时增强了Cx43的转运功能。薯蓣皂苷通过刺激Cx43，显著抑制B16细胞的迁移和侵袭能力，显著降低B16细胞和动物肿瘤组织中肿瘤干细胞的多能性标志物和上皮-间质转化。相反，薯蓣皂苷通过增加M2至M1表型转变来改善促炎细胞因子（IL-6、TNF α和IL-1 β）的分泌以及肿瘤相关巨噬细胞的吞噬能力。更引人注目的是，即使在Cx43功能缺陷的B16和RAW264.7细胞中，薯蓣皂苷仍然显著地逆转了加重的肿瘤恶性程度和降低的巨噬细胞吞噬活性。采用两种经典的肺转移动物模型进行体内实验，结果表明薯蓣皂苷具有显著的抗肺转移作用，其作用与原位肿瘤和转移肺结中Cx43的表达密切相关。总之，薯蓣皂苷靶向Cx43以抑制肿瘤细胞恶性程度并激活巨噬细胞敏感性，从而靶向黑色素瘤微环境。
Connexin 43 (Cx43), a vital gap junction protein in tumor microenvironment (TME), is a novel molecular target for melanoma chemotherapeutics due to its tumor suppressive function. Dioscin, an herbal steroidal saponin, exerts anti-tumor effects while the underlying mechanism is unclear. Using WB, FACS, and immunofluorescence methodologies, we found dioscin significantly activated the transcription and translation of Cx43 via the retinoid acid signaling pathway and simultaneously enhanced the transporting function of Cx43. Through stimulating Cx43, dioscin remarkably suppressed the migratory and invasive capacities of B16 cells, and notably decreased pluripotency markers of cancer stem cells and epithelial-to-mesenchymal transition in B16 cells and animal tumor tissues. Conversely, dioscin improved the secretion of pro-inflammatory cytokines (IL-6, TNF alpha, and IL-1 beta), and the phagocytic capacity of tumor-associated macrophages by increasing M2-to-M1 phenotype transition. More strikingly, even in Cx43 functional deficient B16 and RAW264.7 cells, dioscin still dramatically reversed the aggravated tumor malignancy and reduced macrophage phagocytic activity. Two classical metastasis animal models were utilized in vivo and results showed that dioscin showed significant anti-metastatic effects, which is closely related to the expression of Cx43 either in in situ tumor or metastatic lung nodes. In conclusion, dioscin targets Cx43 to suppress the tumor cell malignancy and activate macrophage sensitivity, thereby targeting melanoma microenvironment.