口腔鱗狀細胞癌（Oral squamous-cell carcinoma, OSCC）的轉移（Metastasis）常造成診斷和治癒的困難。OSCC的轉移和基質金屬蛋白酶-9（Matrix metalloproteinase, MMP）的表現有密切的關係，因此抑制其表現已成為當今治療癌症轉移的目標。先前我們的研究指出用來抑制細菌生長的抗生素-強力黴素（Doxycycline, DOX），可抑制口腔癌細胞珠SCC-15的MMP-9基因的表現，但其機制尚未明瞭。我們初步發現乙型轉型生長因子-1（Transforming growth factor-beta 1, TGF-β1）誘導MMP-9表現的作用可以被DOX顯著地抑制。故本研究假設DOX可能藉由影響TGF-β1的訊號傳遞達到抑制MMP-9的表現。結果顯示DOX不影響Smad3磷酸化作用而影響Smad3/Smad4複合物的形成，最後出現Smad3無法累積在細胞核的現象，而Smad4 siRNA 敲除（Knock down）實驗顯示Smad4對於DOX抑制效果相當重要。因此我們發現DOX可以影響TGF-β1/Smad pathway誘導MMP-9表現的作用，且Smad4可能是DOX結合作用的目標。

The metastasis of cancer is the main problem in the treatment now. Even with the surgery, the prognosis is still worse. Among all types of cancer, the oral squamous-cell carcinoma (OSCC) is the well known for its violent metastasis. According to the report, the ability of OSCC metastasis is related to the performance of matrix metalloproteinase (MMP)-9. Therefore MMP expression suppression had become the target of the treatment of oral cancer. Doxycycline (DOX) was reported to suppress invasion in SCC-15 of OSCC cell line by down-regulating expression of MMP-9. The mechanism of anti-metastasis effect of DOX in OSCC has been considered that DOX reduced MMP-9 at the transcriptional level, but the detail remains to be unclear. In this research, we found that DOX inhibits TGF-β1-induced MMP-9 expression significantly. The objective of this study is to explore the hypothesis that DOX may suppress MMP-9 expression through influencing the signal transduction of TGF-β1 in SCC-15. The result shows DOX do not inhibit phosphorylation of Smad3, but DOX can affect TGF-β1 induced Smad3/Smad4 complex formation. Therefore Smad3 do not accumulate in nuclear. Additionally the MMP-9 of DOX inhibition disappeared in Smad4 silencing condition. We suggested DOX significantly inhibit MMP-9 expression through TGFβ1/Smad signaling pathway, and Smad4 plays an important role in MMP-9 expression of DOX inhibition.

沈領昌。2010。基質金屬蛋白酶在口腔腫瘤之研究，博士論文。國立成功大學生物科技研究所碩博士班。
陳和儒。2011。四環黴素類藥物抑制基質金屬蛋白酶表現和癌細胞生長研究，碩士論文。國立成功大學化學系碩博士班。
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