薑黃素抑制大腸直腸癌細胞轉移之機轉

Abstract

在許多已開發國家，因為飲食習慣的改變，致使大腸直腸癌的發生率逐漸增加，成為人類死亡的主要威脅之一。臨床上對於大腸直腸癌的主要治療方式為：外科手術切除原位腫瘤或配合使用化學治療和放射治療來殺死轉移的癌細胞。然而，癌症的轉移仍是造成大腸直腸癌病人死亡的主要原因。薑黃素(curcumin)應用於人類的醫療已經有上千年的歷史，是一種非常重要的傳統藥物。一直以來，薑黃素被認為可以治療許多包含癌症在內的人類疾病。近年來有許多研究證實薑黃素能夠抑制腫瘤細胞的許多生理特性，但是其調控的機制尚不清楚。本研究主要探討薑黃素對抗大腸直腸癌轉移的機制。首先，我們發現在大腸直腸癌細胞株HCT-116中，給予次致死劑量的薑黃素(0-20 &micro;M)，可以有效抑制細胞的移動能力(於20 &micro;M 有85.2%的抑制性)以及細胞的侵襲能力(於20 &micro;M 有99%的抑制性)，除此之外，我們也發現薑黃素可以有效抑制大腸直腸癌細胞轉移到肝臟的能力。接著，我們使用基因表現晶片探討會受薑黃素調控的基因。經由統計分析(p<0.05, FDR)發現，相對於控制組，共有1239個基因在有薑黃素(20μM)的情況下，其表現量會有兩倍以上的差異。利用MetaCore軟體進一步分析基因的傳導網絡，我們發現細胞貼附、細胞骨架重組以及Sp1轉錄因子的調控網路都可能參與調控薑黃素所引發的抗癌作用。進一步分子生物實驗結果顯示，細胞貼附及細胞骨架重組這兩個訊息傳導的關鍵分子-FAK蛋白會受到薑黃素的抑制。而Sp1轉錄因子的轉錄能力也會受到薑黃素的調控而下降，進而使下游的基因轉錄也受到抑制。由本研究的實驗結果發現，薑黃素對抗大腸直腸癌細胞轉移的能力可能是透過抑制FAK蛋白的訊息路徑和降低Sp1轉錄因子的轉錄能力。

Colon cancer has become a serious threat to public health due to the changes of the dietary habits in many developed countries. In clinic, the standard therapeutic strategies for colon cancers are complete surgery resection for local diseases, and systematic chemotherapy and radiotherapy for metastatic diseases. However, tumor metastasis is the primary cause resulting in cancer death. Curcumin has been used as an important traditional medicine in almost any kind of illness including cancers. Over the past years, curcumin has been proved to be a multifunctional chemotherapeutic agent. However, the anti-tumor mechanism of curcumin is not completely understood yet. In this study, we investigate the underlying anti-metastasis mechanism of curcumin in colorectal cancer. Our results showed that sub-lethal dose (0-20 &micro;M) of curcumin could inhibit cell migration (85.2% of inhibition at 20 &micro;M) and cell invasion (99% of inhibition at 20 &micro;M) in a dose-dependent manner in colon cancer cells. Additionally, curcumin inhibited liver metastasis of colorectal cancer in vivo. The differentially expressed genes of colon cancer cells treated with 20 &micro;M curcumin were analyzed by Affymetrix genechip compared with mocks. There are 1,239 genes with greater than 2-fold change (p<0.05, FPR). The microarray analysis by using MetaCore software indicated that cell adhesion pathway, cytoskeleton remodeling pathway and Specificity protein-1(Sp1) transcriptional regulation may be involved in the anti-metastasis activity of curcumin. Our results showed that FAK signaling pathway which mediates cell adhesion and cytoskeleton remodeling was repressed by curcumin. Besides, the Sp1 transcriptional activity was found to be inhibited by curcumin. These findings suggest that curcumin might execute anti-metastasis activity by down-regulation of Sp1 transcriptional activity and suppression of FAK signaling.