Department of Clinical Nutrition, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Department of Clinical Nutrition, Shanghai No.9 People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200011, China.
Biochimie. 2019 Jul;162:107-115. doi: 10.1016/j.biochi.2019.03.004. Epub 2019 Mar 12.
Triple-negative breast cancer (TNBC) is a heterogeneous group of breast cancer with one common feature: distinctly metastatic nature with higher rate of relapse and shorter survival compared with other subtypes of breast cancer. The epithelial to mesenchymal transition (EMT) is highly associated with cancer metastasis. Cyanidin-3-glucoside (C3G), the most abundant anthocyanin pigment enriched in fresh fruits and vegetables, showed ideal anti-oxidant property. C3G could also inhibit certain malignant behaviors of cancer cells, however, whether repression of EMT was involved in its anti-cancer especially TNBC effect remains unknown. Herein, we report that C3G decreases the migratory and invasive nature of TNBC lines MDA-MB-231 and BT-549. Mechanistically, C3G induces reversion of EMT characterized by phenotype modulation with increased epithelial marker E-ca and ZO-1, decreased mesenchymal marker Vimentin, N-ca and EMT-associated transcription factors Snail1, Snail2. NF-κB is pivotal for EMT and Sirt1 is a NF-κB inhibitor. We show that NF-κB is attenuated and Sirt1 is induced by C3G in TNBC, respectively. And later evidence demonstrates that abrogation of Sirt1 with small interfering RNA transfection abolished NF-κB inhibition and EMT reversion by C3G. Subsequently, we show that microRNA-138(miR-138) represses Sirt1 via mRNA translation inhibition and is inhibited by C3G. Moreover, miR-138 repression is involved in Sirt1 re-activation and migratory and invasive inhibition of TNBC by C3G. Taken together, we supplied more evidence to the anti-breast cancer mechanisms of C3G.
三阴性乳腺癌（TNBC）是一组具有共同特征的异质性乳腺癌：与其他乳腺癌亚型相比，具有明显的转移性，复发率更高，生存率更短。上皮间质转化（EMT）与癌症转移高度相关。矢车菊素-3-葡萄糖苷（C3G）是一种在新鲜水果和蔬菜中含量丰富的最丰富的花色苷色素，具有理想的抗氧化特性。C3G 还可以抑制癌细胞的某些恶性行为，但抑制 EMT 是否参与其抗癌作用，尤其是 TNBC 作用尚不清楚。在此，我们报告 C3G 降低了 TNBC 细胞系 MDA-MB-231 和 BT-549 的迁移和侵袭特性。从机制上讲，C3G 诱导 EMT 的逆转，表现为上皮标记物 E-ca 和 ZO-1 增加，间充质标记物波形蛋白、N-ca 和 EMT 相关转录因子 Snail1、Snail2 减少的表型调节。NF-κB 对于 EMT 至关重要，而 Sirt1 是 NF-κB 的抑制剂。我们表明，C3G 分别减弱了 TNBC 中的 NF-κB 并诱导了 Sirt1。后来的证据表明，用小干扰 RNA 转染阻断 Sirt1 可消除 C3G 对 NF-κB 抑制和 EMT 逆转的作用。随后，我们表明，miR-138 通过抑制 mRNA 翻译来抑制 Sirt1，并被 C3G 抑制。此外，miR-138 的抑制参与了 C3G 对 TNBC 的 Sirt1 再激活以及迁移和侵袭的抑制作用。总之，我们为 C3G 的抗乳腺癌机制提供了更多证据。
