探討兒茶素與吉非替尼合併使用的抗口腔癌細胞轉移分子機制

CMUR > College of Dentistry > Scoll of Dentistry and Graduate Institute of Dental Sciences > Theses & dissertations > Item 310903500/50229

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Title:	探討兒茶素與吉非替尼合併使用的抗口腔癌細胞轉移分子機制 Evaluating molecular mechanism of anti-metastasis on oral cancer cell by EGCG and gefitinib
Authors:	張加明;Chia-Ming Chang
Contributors:	牙醫學系碩士班
Keywords:	兒茶素;吉非替尼;協同作用;遷移;侵入;頭頸鱗狀上皮細胞癌;基質金屬蛋白?-2;兒茶素;吉非替尼;協同作用;遷移;侵入;頭頸鱗狀上皮細胞癌;基質金屬蛋白?-2;epigallocatechin gallate;gefitinib;synergistic effect;migration;invasion;head and neck squamous cell carcinoma;matrix metalloproteinase-2
Date:	2013-07-29
Issue Date:	2013-10-02 10:56:37 (UTC+8)
Publisher:	中國醫藥大學
Abstract:	在過去的十年，人類頭頸部鱗狀上皮細胞癌已成為造成死亡最主要的原因，主要是在於具有相當程度轉移的可能性及治療上的困難。吉非替尼是一種酪胺酸激?抑制劑，已經被證實具有減少口腔癌細胞轉移的治療效果。過去文獻曾提及綠茶中的多酚類化合物-綠茶兒茶素，對於腫瘤具有預防的能力且可以抗癌。然而合併使用吉非替尼及綠茶兒茶素對於人類口腔癌細胞轉移的影響及其機轉仍未清楚。在本研究中，我們試圖去利用CAL 27口腔癌細胞去研究吉非替尼和綠茶兒茶素之協同作用及闡明細胞侵犯及轉移的分子機制。研究中以細胞侵入分析技術及細胞癒合刮傷分析技術方法，發現吉非替尼和綠茶兒茶素單獨使用時，皆有抑制CAL27口腔癌細胞侵犯及轉移的作用；當兩者合併使用時具有協同作用。相同地也發現吉非替尼併用綠茶兒茶素會減少CAL 27口腔癌細胞內基質金屬蛋白?-2的酵素活性及蛋白質表現。此外，研究結果也證實綠茶兒茶素和吉非替尼合併處理的 CAL27 口腔癌細胞會藉由抑制表皮生長因子受體的磷酸化，進而影響下游蛋白質 ERK, JNK, p38, AKT 的磷酸化達到抑制癌細胞轉移的效果。利用基因晶片分析的方法發現合併綠茶兒茶素及吉非替尼可改變及抑制轉移作用及相關基因的改變。重要的是我們也發現在頭頸鱗狀上皮細胞癌的CAL 27細胞株實驗中，綠茶兒茶素可能可以增加艾吉非替尼抑制表皮生長因子接受器磷酸化的敏感度。總的來說，本研究的結果認為吉非替尼和綠茶併用對於抑制癌細胞轉移的協同作用主要是在調控有絲分裂活化蛋白質激?的路徑。這些新的發現對於合併吉非替尼和綠茶兒茶素的治療，可用來抑制口腔癌惡化的協同機制提供更多的了解。 Human head and neck squamous cell carcinoma (HNSCC) is a major cause of cancer-related death during the last decade due to its related metastasis and poor treatment outcomes. Gefitinib (Iressa), a tyrosine kinase inhibitor has been reported to reduce the metastatic abilities of oral cancer. Previous studies have shown that epigallocatechin gallate (EGCG), a green tea polyphenol, possesses cancer chemo?preventive and anticancer activity. However, the mechanisms involved in the suppression of invasion and metastasis of human oral cancer cells following co-incubation with gefitinib and EGCG remain poorly understood. In the present study, we attempted to investigate the synergistic effects of a combined treatment of gefitinib and EGCG in CAL-27 cells in vitro and to elucidate the underlying molecular mechanisms associated with the suppression of cell migration and invasion. In the present study, we found that the individual treatments or the combined treatment of gefitinib and EGCG synergistically inhibited the invasion and migration of CAL-27 cells using transwell inva?sion and wound-healing scratch assays, respectively. Similarly, gefitinib in combination with EGCG synergistically attenuated enzymatic activity and the protein expression of MMP-2 in CAL-27 cells. Furthermore, individual or combined treatment with EGCG and gefitinib suppressed the protein expression of p-EGFR and the phosphorylated protein levels of ERK, JNK, p38 and AKT and displayed inhibitory effects on metastatic ability of CAL-27 cells. Combined effects of EGCG and gefi-tinib-altered anti-metastatic actions for related gene expression were observed using DNA microarray analysis. Importantly, EGCG sensitizes CAL-27 cells to gefitinib-suppressed phosphorylation of epidermal growth factor receptor (EGFR in vitro. Taken together, our results suggest that the synergistic suppression of the metastatic ability of CAL-27 cells after EGCG and gefitinib individual or combined treatment are mediated through mitogen-activated protein kinase (MAPK) signaling. Our novel findings provide potential insights into the mechanism involved with synergistic responses of gefitinib and EGCG against the progression of oral cancer.
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