Institute of Biotechnology, National Cheng Kung University, Tainan, Taiwan.
Oral Oncol. 2010 Mar;46(3):178-84. doi: 10.1016/j.oraloncology.2009.11.013. Epub 2009 Dec 29.
Regional lymph node and distant organ metastasis of oral squamous-cell carcinoma (OSCC) has been associated with increased production of matrix metalloproteases (MMPs), and scientific data showed that doxycycline (Dox) could down-regulate the expression of MMPs. The objective of this study was to evaluate the effect of Dox on the expression of MMPs in vitro using the SCC-15 cell line and in vivo SCC-15 xenografted nude mice. SCC-15 cells maintained under distinct culture conditions expressed high levels of pro-MMP-2 and pro-MMP-9; however, as determined by zymography and Western blot analysis, Dox significantly reduced the production of pro-MMP-2 and pro-MMP-9 after 24h of treatment in a dose-dependent manner (2.5-40 microg/ml). Dox (10 microg/ml) decreased the expression of MMP-9 mRNA but did not alter the level of MMP-2 mRNA after 24h of treatment. In addition, this drug significantly inhibited the invasive and migration activities of SCC-15 cells in vitro (>75% inhibition at 10 microg/ml). On the other hand, daily administration of Dox (3mg/mice) restrained tumor growth in SCC-15 xenografted nude mice, with an inhibition rate of 85.6%. Compared with the control group (treated with normal saline), MMP-9 mRNA levels in the fresh tumor tissue decreased upon Dox treatment (P<0.01) while MMP-2 mRNA levels were unchanged. In conclusion, reduced expression of MMP-9 at the transcriptional level and MMP-2 at the post-transcriptional level caused by Dox was found to be associated with decreased invasion of oral SCC in vitro. Moreover, Dox exerted a significant suppressive effect on tumor growth in an in vivo nude mice model. Taken together, these results, to our knowledge, may first imply that Doxycycline has an adjuvant therapeutic effect on OSCC that is associated with inhibition of MMPs expression.
口腔鳞状细胞癌（OSCC）的区域淋巴结和远处器官转移与基质金属蛋白酶（MMPs）的大量产生有关，科学数据表明强力霉素（Dox）可以下调 MMPs 的表达。本研究的目的是使用 SCC-15 细胞系在体外评估 Dox 对 MMPs 表达的影响，并在 SCC-15 异种移植裸鼠体内进行评估。在不同培养条件下维持的 SCC-15 细胞表达高水平的 pro-MMP-2 和 pro-MMP-9；然而，通过酶谱和 Western blot 分析，Dox 在 24 小时的处理中以剂量依赖性方式显著降低了 pro-MMP-2 和 pro-MMP-9 的产生（2.5-40 μg/ml）。Dox（10 μg/ml）在 24 小时的处理后降低了 MMP-9 mRNA 的表达，但不改变 MMP-2 mRNA 的水平。此外，该药物显著抑制了 SCC-15 细胞在体外的侵袭和迁移活性（10 μg/ml 时抑制率超过 75%）。另一方面，每天给予 Dox（3mg/只小鼠）抑制了 SCC-15 异种移植裸鼠的肿瘤生长，抑制率为 85.6%。与对照组（生理盐水处理）相比，Dox 处理后新鲜肿瘤组织中的 MMP-9 mRNA 水平降低（P<0.01），而 MMP-2 mRNA 水平不变。总之，Dox 引起的 MMP-9 在转录水平和 MMP-2 在转录后水平的表达降低与口腔 SCC 的体外侵袭降低有关。此外，Dox 在体内裸鼠模型中对肿瘤生长具有显著的抑制作用。综上所述，这些结果可能首次表明强力霉素对 OSCC 具有辅助治疗作用，与抑制 MMPs 的表达有关。
