口腔癌屬於頭頸癌的一種，絕大多數是由黏膜上的鱗狀細胞惡化而成，且為世界上第六好發的癌症。在台灣，嚼食檳榔與口腔癌的關係密切，約八成口腔癌患者有嚼食檳榔的習慣，而口腔癌的死亡率也在過去十年間成長了18%，使得口腔癌成為台灣亟需關注的一項疾病。口腔癌的轉移通常發生在病程的中後期，造成治療上的困難，連帶降低了患者的五年存活率。因此，釐清導致口腔癌細胞轉移的訊息傳遞機制，對口腔癌的治療應當能有正面的助益。在這篇論文當中，我使用了由原發位腫瘤分離培養出的口腔癌細胞株 ( OC3 cells ) 以及經篩選後較具有侵入性的兩株細胞，OC3-I5 及OC3-IV2 細胞株，以探討造成口腔癌細胞具有侵襲性的機制。實驗結果顯示，抑制MEK-ERK 及 PI3K-AKT 訊息傳遞時，OC3 細胞增生的速度會減緩，但OC3-I5 及OC3-IV2細胞的增生速度卻不會受到影響，表示在OC3-I5 及OC3-IV2 細胞中，存在其他機制以維持細胞的增生能力。因此我進一步證實了Sonic hedgehog 以及數種分泌出細胞外的因子能夠調控口腔癌細胞的增生能力。此外，磷酸化的ERK1/2 以及 AKT在OC3-IV2 細胞內表現量較高，並且能增加細胞的移動能力。由上述結果顯示，較具有侵入性的口腔癌細胞，能夠透過不同的訊息傳遞機制，維持自身的增生及移動能力，進而促進細胞癌化的發生。

Oral squamous cell carcinoma (OSCC) is a major subtype of head and neck squamous cell carcinoma (HNSCC), and also the sixth most common cancer worldwide. In Taiwan, the etiology of OSCC is highly associated with betel nut chewing, and the number of patients suffering from OSCC has increased 18% during the past ten years. Metastasis in OSCC is rare and usually occurs at late stages. Formation of invasive and metastatic tumor is associated with poor clinical prognosis with reduced five-year survival rate. Thus, understanding the mechanisms leading to metastasis of OSCC is crucial in treating the disease. In this thesis, I used oral carcinoma 3 (OC3) cells and two invasive cell lines, OC3-I5 and OC3-IV2 cells, to study the underlying mechanisms of cancer invasiveness. Our results suggested that inhibition of MEK-ERK and PI3K-AKT pathway blocked proliferation of OC3 cells but had no significant effect on the proliferation of OC3-I5 and OC3-IV2 cells. This result suggests that OC3-I5 and OC3-IV2 cells may have gained new mechanisms to sustain proliferation. To this end, we have identified sonic hedgehog (SHH) and a number of soluble factors are involved i¬n the regulation of OC3 cell proliferation. We also found increased phosphorylation of ERK1/2 and AKT in OC3-IV2 cells compared to OC3 and OC3-I5 cells. The increased phosphorylation of ERK1/2 and AKT contributes to the increased motility of OC3-IV2 cells. Together, these findings suggest that the more invasive OC3 cell lines use different mechanisms to ensure their proliferation and migration during oral cancer progression.

Abstract I
中文摘要 II
誌謝 III
Index V
Abbreviations IX
Introduction 1
Material and Methods 10
Reagents 10
Cell lines and cell culture 11
Cell proliferation assay 11
Cell migration assay 12
Protein preparation and western blot analysis 12
Total RNA purification, polymerase chain reaction (PCR) and semi-quantitative real-time PCR (Q-PCR) 13
Protein identification by LC-MS/MS 14
Statistical analysis 16
Results 17
Phosphorylation of ERK1/2 and AKT increased in OC3-IV2 cells 17
Inhibiting pERK1/2 and pAKT do not significantly affect proliferation of the invasive lines 18
Conditioned medium from OC3-IV2 cells partially rescues the reduced proliferation of OC3 cells in the presence of pERK1/2 or pAKT inhibitors 19
SHH promotes proliferation of OC3 cells 19
Other candidates of secreted soluble factors in OC3-IV2 cells 21
Inhibition of pERK1/2 and pAKT decrease the cell migration ability in OC3, OC3-I5 and OC3-IV2 cells 22
Expression level of MMPs is partially associated with ERK and AKT inhibition during cell migration of OC3, OC3-I5 and OC3-IV2 cells 23
Discussion 25
Figures 29
Figure 1. Protein expression in OC3, OECM1, and C9 cell lines 29
Figure 2. Effects of U0126 and LY294002 on the proliferation of OC3, OC3-I5 and OC3-IV2 cells 31
Figure 3. Conditioned medium from OC3-IV2 cells partially rescues the reduced proliferation of OC3 cells caused by ERK and AKT inhibition 33
Figure 4. Expression of SHH signaling in OC3, OC3-I5 and OC3-IV2 cells 36
Figure 5. SHH treatment increases the proliferation of OC3 cells 37
Figure 6. Possible candidates of secreted factors in OC3-IV2 cells 38
Figure 7. Migration of OC3, OC3-I5 and OC3-IV2 cells 40
Figure 8. Inhibition of ERK phosphorylation decreases the cell migration of OC3, OC3-I5 and OC3-IV2 cells 41
Figure 9. Inhibition of AKT phosphorylation decreases the cell migration of OC3, OC3-I5 and OC3-IV2 cells 43
Figure 10. Expression level of MMPs in OC3, OC3-I5 and OC3-IV2 cells 45
Figure 11. Expression level of MMPs after ERK1/2 inhibition in OC3, OC3-I5 and OC3-IV2 cells 47
Figure 12. Expression level of MMPs after AKT inhibition in OC3, OC3-I5 and OC3-IV2 cells 49
Table 51
Table 1. Gene expression analysis by cDNA microarray (by the lab of Professor Lu-Hai Wang) in OC3 and OC3-I5 cells 51
Appendix 52
Figure A1. Increase of Cyclin D1 expression in OC3-I5 and OC3-IV2 cells 52
Table A1. Possible candidates of secreted soluble factors in OC3 cells through LC-MS/MS analysis 54
Table A2. Possible candidates of secreted soluble factors in OC3-IV2 cells through LC-MS/MS analysis 56
Reference 57

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