Tetramethylpyrazine inhibits tumor growth of lung cancer through disrupting angiogenesis via BMP/Smad/Id-1 signaling
Tetramethylpyrazine inhibits tumor growth of lung cancer through disrupting angiogenesis via BMP/Smad/Id-1 signaling
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DOI：
10.3892/ijo.2016.3443
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发表时间：
2016-05-01
影响因子：
5.2
通讯作者：
Fu, Yan
中科院分区：
文献类型：
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作者：
Jia, Youchao;Wang, Zhigang;Fu, Yan
目的：探讨川芎嗪（TMP）抑制肺癌血管生成和肿瘤生长的机制。体外培养的人微血管内皮细胞（HMEC-1）的细胞增殖、迁移和管形成通过3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四唑溴盐（MTT）、伤口愈合、Transwell和Matrigel测定来评价。RT-PCR和Western blotting检测BMP/Smad/Id-1信号的表达。在A549异种移植肿瘤模型中，将TMP（40和80 mg/kg/天）腹膜内注射到小鼠中。免疫组化检测CD 31、Smad 1/5/8磷酸化和Id-1的表达。我们证明TMP以剂量和时间依赖性方式抑制HMEC-1的增殖、迁移和毛细血管形成。此外，TMP（0.4 mg/ml）处理HMEC-1细胞显著上调BMP 2表达，下调BMPRIA、BMPRII、磷酸化Smad 1/5/8和Id-1表达。此外，TMP给药显著抑制裸鼠A549移植瘤的生长。与溶剂相比，TMP处理的异种移植肿瘤中的CD 31、磷酸化Smad 1/5/8和Id-1表达显著抑制。结论：TMP通过阻断BMP/Smad/Id-1信号通路抑制肺癌血管生成和肿瘤生长。
The underlying mechanisms of inhibitory effects induced by tetramethylpyrazine (TMP) on angiogenesis and tumor growth of lung cancer were investigated. In vitro cell proliferation, migration, and tube formation of human microvascular endothelial cells (HMEC-1) were evaluated by a 3-(4,5-dimethylthiazol-2-yl)-2,5-dephenyltetrazolium bromide (MTT), wound healing, Transwell, and Matrigel assays. The expression of BMP/Smad/Id-1 signals was detected by RT-PCR and western blotting. In an A549 xenograft tumor model, TMP (40 and 80 mg/kg/day) was intraperitoneally injected into mice. The expressions of CD31, phosphorylated Smad1/5/8, and Id-1 were measured by immunohistochemistry. We demonstrated that TMP inhibited proliferation, migration, and capillary tube formation of HMEC-1 in a dose-and time-dependent manner. Furthermore, treatment of HMEC-1 cells with TMP (0.4 mg/ml) significantly upregulated BMP2 expression and downregulated BMPRIA, BMPRII, phosphorylated Smad1/5/8, and Id-1 expression. In addition, administrations of TMP remarkably inhibited tumor growth of A549 xenograft in nude mice. The CD31, phosphorylated Smad1/5/8, and Id-1 expression were significantly inhibited in TMP-treated xenograft tumors compared with the vehicle. In conclusion, our results indicated that TMP suppressed angiogenesis and tumor growth of lung cancer via blocking the BMP/Smad/Id-1 signaling.