臺灣博碩士論文加值系統

口腔癌是全球主要的公共衛生問題，易引起高發病率與死亡率。口腔癌特點是容易侵襲腫瘤發生部位並藉由頸淋巴結進行腫瘤轉移。膠質細胞源性神經營養因子(Glial cell line-derived neurotrophic factor)為神經滋養因子家族的成員，其功能可促進多種神經細胞的增生與分化。先前的研究顯示，GDNF可誘導胰腺癌與乳腺癌細胞的侵襲性與黏附性，我們實驗室也發現GDNF可誘導神經膠細胞瘤細胞轉移作用。在本篇研究中，顯示GDNF會誘導人類口腔癌細胞株HSC3與SCC4的細胞轉移。加入GDNF會誘導MMP-9與MMP-13在人類口腔癌的表現。因此，我們利用MMP-9中和性抗體，一般性MMP抑制劑或MMP-9抑制劑會降低GDNF誘導人類口腔癌細胞轉移。再者，我們也利用MMP-13中和性抗體，MMP-13抑制劑或MMP-13 siRNA也會抑制GDNF誘導人類口腔癌細胞轉移。結果顯示，隨著時間增加，GDNF也會誘導ERK、p38與JNK的蛋白表現以及活化AP-1。利用MAP Kinase抑制劑或AP-1抑制劑皆會減少GDNF所誘導基質金屬蛋白酶(MMPs)表現。經由移行分析篩選出具有較高轉移能力的細胞株，發現該細胞株表達較高量GDNF，且利用GDNF的中和性抗體作用，有效拮抗GDNF所誘發的口腔癌細胞轉移。由此結果得知，GDNF可能是經由自我分泌或旁分泌作用促進人類口腔癌的轉移發生，且其誘導人類口腔癌的細胞遷移與MAP kinase的訊息傳遞途徑以及基質金屬蛋白酶(MMPs)的表現有關。

Oral cancer is a major global public health problem, causing high morbidity and mortality. They are characterized by a high degree of local invasiveness and a high rate of metastasis to cervical lymph nodes. Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor that promotes survival and development of various neural cells. Previous studies have shown that GDNF enhances the invasive and adhesive behaviors in pancreatic cancer and breast cancer cells. Our previous reported offers also showed that GDNF induces glioma cell migration. In this study, we found that application of recombinant human GDNF enhances the cell migration in SCC4 and HSC3 human oral cancer cell lines. We also found that the expression of matrix metalloproteinase-9 (MMP-9) protein and secretion in response to GDNF stimulation. The GDNF-induced increase in cell migration was antagonized by MMP-9 neutralizing antibody, general MMP inhibitor (GM6001) or specific MMP-9 inhibitor. Moreover, we found that the expression of matrix metalloproteinase-13 mRNA and secretion in response to GDNF stimulation. The GDNF-induced increase in cell migration was antagonized by MMP-13 neutralizing antibody, specific MMP-13 inhibitor or silencing MMP-13. Moreover, GDNF-induced MMP-13 expression was reduced by ERK inhibitor (PD98059), p38 inhibitor (SP600125) or JNK inhibitor (SB203580). Treatment with GDNF induced ERK, p38 and JNK/c-Jun activation and increased AP-1 DNA binding activity in a time-dependent manner. Treatment with AP-1 inhibitors (tanshinone IIA and curcumin) also reduced GDNF-induced oral cell migration. In addition, we also found that treatment with GDNF neutralizing antibody effectively antagonized GDNF-induced oral cancer cell migration. In migration-prone sublines, oral cancer cells were greater migration ability, and the enhancement were reduced by GDNF-neutralized antibody. These results reveal an autocrine and/or paracrine effect of GDNF in human oral cancer. In conclusion, this study indicates that GDNF enhances oral cancer cell migration and which might through activates MAP kinase pathway and increase MMPs production.

目錄 .................................................................................................................... I
縮寫對照表 ..................................................................................................... IV
中文摘要 ......................................................................................................... VI
英文摘要 ...................................................................................................... VIII
第一章 前言 ................................................................................................... 1
第一節 研究背景 .................................................................................... 1
1.1 口腔癌(oral cancer) .................................................................. 1
1.2 膠質細胞源性神經營養因子(GDNF) ..................................... 6
1.3 基質金屬蛋白酶(MMPs; matrix metalloprotenases) ............ 11
1.4 MAP kinases (Motigen-activated protein kinases；MAPKs) 17
1.5 Activator protein-1(AP-1) ...................................................... 22
第二節 研究目的 .................................................................................. 26
第二章 研究方法 ......................................................................................... 27
第一節 實驗材料 .................................................................................. 27
2.1.1 實驗細胞株............................................................................. 27
2.1.2 細胞培養(cell culture) ............................................................ 27
2.1.3 細胞移行分析(migration assay) ............................................ 27
2.1.4 反轉錄聚合酶連鎖反應(RT-PCR) ........................................ 27
II
2.1.5 細胞轉染(transfection) ........................................................... 28
2.1.6 細胞蛋白核質分離(nuclear/cytosolic extract) ...................... 28
2.1.7 凝膠電泳遷移改變實驗(EMSA) ........................................... 28
2.1.8 西方墨點法(Western blot) ..................................................... 29
2.1.9 抗體(antibody) ........................................................................ 29
2.1.10 重組蛋白和抑制劑(recombinant protein and inhibitor) ........ 30
第二節 實驗方法 .................................................................................. 30
2.2.1 細胞培養................................................................................. 30
2.2.2 細胞移行法(transwell assay) ................................................. 30
2.2.3 西方墨點法(Western blot) ..................................................... 31
2.2.4 RNA抽取 ............................................................................... 31
2.2.5 反轉錄聚合酶連鎖反應(RT-PCR) ........................................ 32
2.2.6 明膠酶譜檢測(gelatin zymography) ...................................... 32
2.2.7 細胞轉染(transfection) ........................................................... 33
2.2.8 細胞蛋白核質分離(nuclear/cytosolic extract) ...................... 33
2.2.9 凝膠電泳遷移改變實驗(EMSA) ........................................... 34
2.2.10 免疫組織染色 ........................................................................ 34
第三章 實驗結果 ........................................................................................... 35
3.1 GFR??1與Ret參與GDNF誘導口腔癌細胞轉移的作用 .. 35
III
3.2 GDNF誘導口腔癌細胞轉移的作用是與MMPs有關 ....... 36
3.3 MAP kinase訊息傳遞路徑參與GDNF誘導口腔癌細胞轉移的作用 ............................................................................................... 37
3.4 c-Jun與轉錄因子AP-1參與在GDNF誘導口腔癌細胞轉移的作用 ............................................................................................... 37
3.5 轉移能力較強的口腔癌細胞高度表現GDNF .................... 38
第四章 結論 ................................................................................................... 39
圖表 ................................................................................................................. 40
參考文獻 ......................................................................................................... 48

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