Berberine Reverses Epithelial-to-Mesenchymal Transition and Inhibits Metastasis and Tumor-Induced Angiogenesis in Human Cervical Cancer Cells
Berberine Reverses Epithelial-to-Mesenchymal Transition and Inhibits Metastasis and Tumor-Induced Angiogenesis in Human Cervical Cancer Cells
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DOI：
10.1124/mol.114.094037
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发表时间：
2014-12-01
影响因子：
3.6
通讯作者：
Chen, Pei-Ni
中科院分区：
文献类型：
--
作者：
Chu, Shu-Chen;Yu, Cheng-Chia;Chen, Pei-Ni
转移是癌症患者死亡的最常见原因，而上皮-间质转化（EMT）是癌症转移所必需的，这是一个多步骤的复杂过程，包括局部浸润、内渗、外渗和远处部位的增殖。当癌细胞转移时，血管生成也是转移性传播所需的，因为血管密度的增加将允许肿瘤细胞更容易进入循环，并且代表了治疗干预的合理靶点。小檗碱具有多种抗炎和抗癌的生物学作用。在这项研究中，我们提供了分子证据，表明小檗碱的抗转移作用，显示几乎完全抑制高转移性SiHa细胞的侵袭（P < 0.001），通过降低基质金属蛋白酶-2和尿激酶型纤溶酶原激活剂的转录活性。小檗碱可逆转转化生长因子β 1诱导的EMT，并引起E-钙粘蛋白等上皮标志物上调，并抑制N-钙粘蛋白和snail-1等间充质标志物。通过snail-1特异性小干扰RNA选择性抑制snail-1也显示SiHa细胞中E-cadherin表达增加。小檗碱还减少肿瘤诱导的血管生成在体外和体内。重要的是，体内BALB/c裸鼠异种移植模型和尾静脉注射模型显示，小檗碱治疗通过口服管饲法分别减少肿瘤生长和肺转移。综上所述，这些发现表明小檗碱可以减少宫颈癌细胞的转移和血管生成，从而构成转移控制的辅助治疗。
Metastasis is the most common cause of cancer-related death in patients, and epithelial-to-mesenchymal transition (EMT) is essential for cancer metastasis, which is a multistep complicated process that includes local invasion, intravasation, extravasation, and proliferation at distant sites. When cancer cells metastasize, angiogenesis is also required for metastatic dissemination, given that an increase in vascular density will allow easier access of tumor cells to circulation, and represents a rational target for therapeutic intervention. Berberine has several anti-inflammation and anticancer biologic effects. In this study, we provided molecular evidence that is associated with the antimetastatic effect of berberine by showing a nearly complete inhibition on invasion (P < 0.001) of highly metastatic SiHa cells via reduced transcriptional activities of matrix metalloproteinase-2 and urokinase-type plasminogen activator. Berberine reversed transforming growth factor-beta 1-induced EMT and caused upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and snail-1. Selective snail-1 inhibition by snail-1-specific small interfering RNA also showed increased E-cadherin expression in SiHa cells. Berberine also reduced tumor-induced angiogenesis in vitro and in vivo. Importantly, an in vivo BALB/c nude mice xenograft model and tail vein injection model showed that berberine treatment reduced tumor growth and lung metastasis by oral gavage, respectively. Taken together, these findings suggested that berberine could reduce metastasis and angiogenesis of cervical cancer cells, thereby constituting an adjuvant treatment of metastasis control.