Berberine Suppresses Cell Motility Through Downregulation of TGF-β1 in Triple Negative Breast Cancer Cells
Berberine Suppresses Cell Motility Through Downregulation of TGF-β1 in Triple Negative Breast Cancer Cells
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DOI：
10.1159/000487171
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Lee, Jeong Eon
中科院分区：
文献类型：
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作者：
Kim, Sangmin;Lee, Jeongmin;Lee, Jeong Eon
背景/目标：转化生长因子-β 蛋白 (TGF-β) 是多功能生长因子，是多种癌症类型（包括乳腺癌和肺癌细胞）上皮-间质转化 (EMT) 的强大调节剂。在这里，我们证明了小檗碱 (BBR) 通过抑制 TGF-β 1 表达对三阴性乳腺癌 (TNBC) 细胞的肿瘤生长和转移的抑制作用。方法：通过实时PCR分析mRNA表达水平。分别通过酶谱法和共聚焦显微镜分析MMP-2、MMP-9和TGF-β1蛋白表达水平。通过伤口愈合测定来分析细胞迁移。使用异种移植模型分析 TNBC 细胞的致瘤性，例如肿瘤生长和转移。结果：在临床数据集中，异常的 TGF-β1 表达与乳腺癌患者的不良预后相关。我们使用 TNBC 细胞的体外结果表明，TGF-β 1 处理可增加基质金属蛋白酶 (MMP)-2 和 MMP-9 的表达水平以及细胞迁移能力。相比之下，MMP-2 和 MMP-9 的基础水平被特定的 TGF-β 受体 I 抑制剂 SB431542 抑制。此外，SB431542 降低了 TGF-β1 诱导的 MMP-2 和 MMP-9 表达以及细胞迁移。有趣的是，我们首次证明 BBR 降低了 TNBC 细胞中 TGF-β 1 的水平，但不降低 TGF-β 2 的水平。此外，BBR 显着降低了 TNBC 细胞中 MMP-2 表达水平以及细胞迁移能力。最后，我们在 MDA-MB231 和 4T1 乳腺癌异种移植模型中检查了 BBR 对体内肿瘤生长和肺转移的影响，结果表明，BBR 治疗后两者均显着下降。结论：BBR通过抑制TGF-β1表达来抑制TNBC细胞的致瘤性。因此，我们证明 BBR 可能是治疗 TNBC 的有前途的药物。 (C) 2018 作者由巴塞尔 S. Karger AG 出版
Background/Aims: Transforming growth factor-beta proteins (TGF-beta s) are multifunctional growth factors and powerful modulators of the epithelial-mesenchymal transition (EMT) in a variety of cancer types including breast and lung cancer cells. Here, we demonstrated the inhibitory effect of berberine (BBR) on tumor growth and metastasis of triple negative breast cancer (TNBC) cells via suppression of TGF-beta 1 expression. Methods: The levels of mRNA expression were analyzed by real-time PCR. The levels of MMP-2, MMP-9 and TGF-beta 1 protein expression were analyzed by zymography and confocal microscopy, respectively. Cell migration was analyzed by wound healing assay. Tumorigenicity of TNBC cells such as tumor growth and metastasis was analyzed using xenograft models. Results: In a clinical data set, aberrant TGF-beta 1 expression was associated with poor prognosis of breast cancer patients. Our in vitro results using TNBC cells showed that the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 and the capacity for cell migration were increased by TGF-beta 1 treatment. In contrast, basal levels of MMP-2 and MMP-9 were suppressed by a specific TGF-beta receptor I inhibitor, SB431542. In addition, TGF-beta 1-induced MMP-2 and MMP-9 expression and cell migration were decreased by SB431542. Interestingly, we showed for the first time that BBR decreased the level of TGF-beta 1, but not TGF-beta 2, in TNBC cells. Furthermore, BBR significantly decreased the level of MMP-2 expression as well as the capacity for cell migration in TNBC cells. Finally, we examined the effect of BBR on in vivo tumor growth and lung metastasis in MDA-MB231 and 4T1 breast cancer xenograft models and showed that both were significantly decreased following BBR treatment. Conclusion: BBR suppresses tumorigenicity of TNBC cells through inhibition of TGF-beta 1 expression. Therefore, we demonstrate that BBR could be a promising drug for treatment of TNBC. (C) 2018 The Author(s) Published by S. Karger AG, Basel