Bovine lactoferrin reverses programming of epithelial-to-mesenchymal transition to mesenchymal-to-epithelial transition in oral squamous cell carcinoma
Bovine lactoferrin reverses programming of epithelial-to-mesenchymal transition to mesenchymal-to-epithelial transition in oral squamous cell carcinoma
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DOI：
10.1016/j.bbrc.2018.10.193
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发表时间：
2018-12-09
影响因子：
3.1
通讯作者：
Takata, Takashi
中科院分区：
文献类型：
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作者：
Chea, Chanbora;Miyauchi, Mutsumi;Takata, Takashi
上皮间质转化（EMT）是包括口腔鳞状细胞癌（OSCC）在内的肿瘤侵袭和转移的生物学过程。然而，尚未发现直接靶向EMT的有效抗癌药物。因此，我们的目的是研究牛乳铁蛋白（bLF）对EMT的抑制作用，以实现间充质上皮转化（MET）在口腔鳞癌。OSCC细胞系HOC 313（EMT诱导）和SCCVII（无EMT诱导）用bLF处理。bLF对口腔鳞癌EMT的影响通过苏木精和伊红染色进行组织学鉴定，并使用抗E-钙粘蛋白抗体进行形态学和免疫组化观察。RT-PCR和Western blotting检测E-cadherin和vimentin的表达水平。E-cadherin的免疫表达在体内C3 H/HeN小鼠的肿瘤组织中进行了检查，移植SCCVII细胞，有或没有bLF管理。我们发现，bLF改变梭形间充质细胞立方样上皮细胞和增强膜结合的E-cadherin在HOC 313细胞的亲和力。EMT-MET在HOC 313细胞中的转化通过E-cadherin的上调和波形蛋白的抑制来证实。此外，bLF通过下调ERK 1/2磷酸化抑制TWIST表达。此外，在经口给予bLF的小鼠异种移植物中观察到抑制肿瘤细胞浸润和增加E-钙粘蛋白表达。因此，基于体外和体内研究的结果，我们得出结论，bLF通过MET引起上皮特性的恢复。重要的是，这一发现是新的，是第一个报告表明，bLF抑制EMT和诱导MET在口腔鳞癌，表明bLF可能提供一种新的治疗策略在口腔鳞癌。(C)2018爱思唯尔公司All rights reserved.
Epithelial-to-mesenchymal transition (EMT) is a biological process of invasion and metastasis in cancers, including in oral squamous cell carcinoma (OSCC). However, an effective anticancer drug that directly targets EMT has not yet been discovered. Therefore, we aimed to investigate the repressive effects of bovine lactoferrin (bLF) on EMT to achieve mesenchymal-to-epithelial transition (MET) in OSCC. OSCC cell lines, HOC313 (EMT-induced) and SCCVII (without EMT induction), were treated with bLF. The effects of bLF on EMT in OSCC were identified histologically by haematoxylin and eosin staining and observed morphologically and immunohistochemically using an anti-E-cadherin antibody. Expression levels of E-cadherin and vimentin were investigated using RT-PCR and western blotting. Immuno-expression of E-cadherin was examined in vivo in tumour tissues of C3H/HeN mice, transplanted with SCCVII cells, with or without bLF administration. We found that bLF changed the spindle-like mesenchymal cells to cuboidal-like epithelial cells and enhanced the affinity of membrane-bound E-cadherin in HOC313 cells. The transformation of EMT-MET in HOC313 cells was confirmed by the upregulation of E-cadherin and suppression of vimentin. Moreover, bLF suppressed TWIST expression through downregulation of ERK1/2 phosphorylation. Additionally, the inhibition tumour cell infiltration and increase in E-cadherin expression were observed in xenografts of the mice orally administered with bLF. Thus, based on the results from in vitro and in vivo studies, we concluded that bLF caused the restoration of epithelial properties through MET. Importantly, this finding is novel and is the first report indicating that bLF inhibited EMT and induced MET in OSCC, suggesting that bLF may provide a novel therapeutic strategy in OSCC. (C) 2018 Elsevier Inc. All rights reserved.