現今的抗表皮生長因子受體 (epidermal growth factor receptor (EGFR)) 療法對於口腔癌的治療，因為口腔癌的抗藥性和表皮生長因子受體表現量減少，使得此療法無法得到良好的效果。在此篇研究中我們證明了致癌基因 ROS1 能夠扮演口腔麟狀細胞癌 (oral squamous cell carcinoma (OSCC)) 轉移的驅動者，以其作為另一個治療的標的。我們檢視了 188 個口腔癌病人的腫瘤檢體，發現了 ROS1 的表現量上升與腫瘤轉移至肺和淋巴結的發生有高度的相關性。機制研究方面顯示，ROS1 的活化起因於大量的 ROS1 基因表現，而非基因重組所造成，此發現和其他癌症中所發現的現象不同。我們的結果進一步地顯示，在具有高度侵襲性 (invasion) 的口腔麟狀癌細胞中，組織蛋白甲基轉移酶 (histone methyltransferase) EZH2 的表現量下降會引起組蛋白 H3 第二十七離胺酸三個甲基化修飾 (histone H3 lysine 27 trimethylation) 下降以及染色質體鬆開，並且誘導轉錄因子 STAT1 結合至 ROS1 目標基因 CXCL1 的增強子 (enhancer) 和 GLI1 的內含子 (intron)，進而促進這兩個目標基因的表現。在口腔癌細胞小鼠尾部靜脈注射和口腔異種移植腫瘤動物模式中，具有高度侵襲性的口腔麟狀癌細胞中的 ROS1 表現量下降能夠降低癌細胞增生的能力以及抑制癌細胞轉移至肺。我們的研究結果顯示，ROS1 能夠作為口腔麟狀細胞癌的生物標記以及治療標靶。最後，我們證明了同時攻擊 ROS1 和表皮生長因子受體的療法能夠作為治療口腔癌的有效方針。

Current anti-epidermal growth factor receptor (EGFR) therapy for oral cancer does not provide satisfactory efficacy due to drug resistance or reduced EGFR level. As an alternative candidate target for therapy, here we identified an oncogene, ROS1, as an important driver for oral squamous cell carcinoma (OSCC) metastasis. Among tumors from 188 oral cancer patients, upregulated ROS1 expression strongly correlated with metastasis to lung and lymph nodes. Mechanistic studies uncover that the activated ROS1 results from highly expressed ROS1 gene instead of gene rearrangement, a phenomenon distinct from other cancers. Our data further reveal a novel mechanism that reduced histone methyltransferase EZH2 leads to a lower trimethylation of histone H3 lysine 27 suppressive modification, relaxes chromatin, and promotes the accessibility of the transcription factor STAT1 to the enhancer and the intron regions of ROS1 target genes, CXCL1 and GLI1, for upregulating their expressions. Down-regulation of ROS1 in highly invasive OSCC cells, nevertheless, reduces cell proliferation and inhibits metastasis to lung in the tail-vein injection and the oral cavity xenograft models. Our findings highlight ROS1 as a candidate biomarker and therapeutic target for OSCC. Finally, we demonstrate that co-targeting of ROS1 and EGFR could potentially offer an effective oral cancer therapy.

Abstract..........................................................I
中文摘要...........................................................II
誌謝..............................................................III
Publication list..................................................VI
Table of contents.................................................VII
Introduction......................................................1
1. Oral cancer....................................................1
1.1 Epidemiology..................................................1
1.2 Cancer progression............................................2
1.3 Cancer therapy................................................3
1.4 Challenge and purpose.........................................4
2. Receptor tyrosine kinases in head and neck squamous cell carcinoma.........................................................5
3. ROS1 oncogene..................................................7
4. Epigenetic regulation and cancers..............................11
4.1 Histone modifications.........................................11
4.2 Histone modifiers.............................................12
4.3 MicroRNAs in oral cancer......................................14
5. Chemokines and cancer progression..............................15
6. Glioma-associated oncongene (GLI)..............................17
Materials and Methods.............................................20
Cell lines........................................................20
Antibodies and reagents...........................................20
Cell proliferation assays.........................................21
In vitro migration and invasion assays............................22
Knockdown of selective genes via RNAi.............................23
Reverse Transcription-PCR and quantitative PCR (Q-RCR)............24
Western blotting..................................................25
Fluorescence in situ hybridization (FISH).........................25
Bisulfite sequencing..............................................26
Chromatin immunoprecipitation (ChIP) assays.......................26
Immunohistochemistry (IHC) analysis and gene expression of patient tissue samples....................................................28
Orthotopic and tail-vein injection of OSCC cells into mice........29
miRNA array analysis..............................................29
Statistical analysis..............................................30
Results...........................................................31
Upregulated ROS1 in highly invasive OSCC cells....................31
Effect of upregulated ROS1 in migration, invasion and lung colonization of OSCC cells........................................34
Synergistic effect of co-treatment of OSCC cells with gefitinib and either foretinib or crizotinib....................................35
Epigenetic regulation of ROS1.....................................36
ROS1-associated oncogenic signaling and novel target genes........39
STAT1-mediated regulation of CXCL1................................41
Effect of ROS1-induced Gli1 expression in cell proliferation and migration/invasion................................................41
Discussion........................................................44
Figures...........................................................49
Figure 1. The correlation of OSCC cell invasion and EGFR expression ..................................................................49
Figure 2. The effect of gefitinib treatment on OSCC cells.........50
Figure 3. Identification of ROS1 in the highly invasive OSCC cell lines.............................................................53
Figure 4. The correlation of ROS1 levels and OSCC cell invasion...54
Figure 5. The clinical relevance of high ROS1 level...............56
Figure 6. Identification of ROS1 gene rearrangement...............58
Figure 7. ROS1 is required for OSCC cell proliferation............59
Figure 8. ROS1 is required for OSCC cell migration and invasion...61
Figure 9. ROS1 is required for OSCC cell growth and lung colonization. ..................................................................62
Figure 10. Inhibitor assays for highly invasive OSCC cells........65
Figure 11. Inhibitory effect of combined treatment with gefitinib and foretinib or crizotinib on OC3 and OC3-IV2 cell proliferation.....66
Figure 12. Inhibitory effect of combined treatment with gefitinib and foretinib or crizotinib on OC3 and OC3-IV2 cell migration and invasion ..................................................................67
Figure 13. Inhibitory effect of combined treatment with gefitinib and foretinib or crizotinib on C9 and C9-IV2 cell proliferation.......68
Figure 14. Inhibitory effect of combined treatment with gefitinib and foretinib on C9 and C9-IV2 cell migration and invasion............69
Figure 15. H3K27me3 modification at the ROS1 promoter.............71
Figure 16. EZH2 levels in highly invasive OSCC cells and EZH2 occupancy at the ROS1 promoter....................................72
Figure 17. Effect of EZH2 knockdown on OSCC cell invasion and on expression of ROS1................................................73
Figure 18. The correlation of EZH2 levels and OSCC cell invasion..74
Figure 19. Identification of miRNAs targeting EZH2 mRNA...........75
Figure 20. Identification of miRNAs targeting ROS1 mRNA...........76
Figure 21. Effect of increased ROS1 on MAPK and PI3K-AKT signaling pathways..........................................................78
Figure 22. Inhibition of MAPK and PI3K-AKT signaling pathways in OSCC cell proliferation, migration, and invasion.......................79
Figure 23. Identification of ROS1 target genes....................80
Figure 24. CXCL1 is required for migration and invasion of OSCC cells. ..................................................................81
Figure 25. STAT1 occupancy at the 5’ region of CXCL1 is regulated by ROS1..............................................................82
Figure 26. Gli1 levels and Hh signaling pathway in highly invasive OSCC cells........................................................83
Figure 27. H3K27me3 modification and EZH2 occupancy at the GLI1 promoter..........................................................84
Figure 28. STAT1 occupancy at the GLI1 gene region is regulated by ROS1..............................................................85
Figure 29. Gli1 is required for OSCC cell proliferation...........87
Figure 30. Effect of EZH2 knockdown on expression of CXCL1 and GLI1 ..................................................................88
Figure 31. Expression of EZH2 mRNA in patients with prostate cancer or OSCC with metastasis..............................................89
Figure 32. Arecoline and ethanol increase ROS1 gene expression in OC3 cells.............................................................90
Figure 33. Schematic model of how ROS1 promotes oral cancer progression.......................................................91
Tables............................................................93
Table 1. List of primers for detection of gene expressions........93
Table 2. List of primers for detection of miRNA expressions.......95
Table 3. List of primers for ChIP assay...........................96
Table 4. Upregulated miRNAs in miRNA array between OC3 and OC3-IV2 cells.............................................................97
Table 5. EZH2-targeting miRNAs....................................98
Table 6. downregulated miRNAs in miRNA array between OC3 and OC3-IV2 cells.............................................................101
Table 7. ROS1-targeting miRNAs....................................102
Table 8. Upregulated genes in microarray between OC3 and OC3-I5 cells ..................................................................103
References........................................................106

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