口腔癌是頭頸癌的一種。大約90%的口腔癌以表皮鱗狀上皮細胞癌(squamous cell carcinoma)為主。有許多因素會導致癌化現象發生，其中包含細胞激素。在腫瘤的微環境中，會產生許多細胞激素，這些細胞激素對於癌症的發生扮演很重要的角色。癌細胞會對於宿主分泌的細胞激素產生反應，進而促進腫瘤生長，減少細胞死亡並加速腫瘤轉移速度。有鑑於此，我想知道哪些細胞激素會影響口腔癌細胞的生長。我利用口腔鱗狀上皮癌細胞株(簡稱OC3細胞)來做以下實驗，此細胞株來自於有多年嚼檳榔但沒有抽菸習慣的口腔癌病人。另外兩株較具有侵入性的細胞株，OC3-I5細胞及OC3-IV2細胞，是用來探討口腔癌的侵襲性機制。 OC3-I5細胞是利用OC3細胞透過體外trans-well assay進行篩選，OC3-IV2細胞是將OC3細胞打入老鼠尾部後，等細胞轉移至肺部形成腫瘤，將腫瘤取出後做細胞培養。在這論文中，我發現interleukin 8受體 (IL-8Rs) 的表現量是OC3-I5細胞的表現量最高，而interleukin 8 (IL-8)的表現量在這三株細胞中並沒有差異。了解IL-8如何調控癌細胞生長的機制，或許能夠為未來癌症治療中如何控制癌細胞的異常生長，帶來一道新的曙光。為此，我發現IL-8可以引起三株細胞中ERK及AKT的磷酸化，卻無法引起STAT3的磷酸化。由於OC3-I5 細胞有較高的IL-8Rs表現量，我發現相較於另外兩株細胞，IL-8能夠明顯促進OC3-I5細胞的增生能力。由IL-8所促進的增生能力，某種程度上受PI3K-AKT及MEK-ERK1/2兩個訊號路徑所調控。相反的，IL-8無法增強口腔癌細胞的移動能力。總結此篇論文結果，OC3-I5細胞的IL-8Rs表現量較高且對於IL-8的刺激，有更明顯的反應，或許有助於促進OC3-I5細胞的癌化過程。

Oral cancer is a subtype of head and neck cancer. More than 90% of oral cancers are squamous cell carcinomas. Many factors contribute to tumorigenesis including cytokines. Cytokines that produced in the tumor microenvironment plays an important role in cancer pathogenesis. Cancer cells can respond to host-derived cytokines and thus promote tumor growth, attenuate apoptosis and facilitate metastasis. In view of this, we set out to determine whether cytokines would affect the growth of oral cancer cells. We used oral carcinoma 3 (OC3) cell lines, which was established from a long-term areca (betel) chewer who did not smoke, as a cell model. Two invasive lines were used to investigate the mechanism of oral cancer cell invasiveness, OC3-I5 and OC3-IV2 cells. OC3-I5 cells were selected through in-vitro trans-well assays. OC3-IV2 cells were isolated from tumors in lung after tail-vein injection of OC3 to mice. In this study, I showed that the expressions of the interleukin 8 receptors (IL-8Rs) were up-regulated in OC3-I5 cells compare to the other two lines, whereas the mRNA levels of the interleukin 8 (IL-8) among the OC3 cell lines were similar. Understanding the mechanisms by which IL-8 regulates cancer cell growth should shed light on the potential therapeutic strategies for controlling oral cancer cell growth. To this end, I found that OC3 cell lines treated with IL-8 induced phosphorylation of AKT and ERK1/2, but not STAT3. In line with the higher expression of IL-8Rs in OC3-I5 cells, I found that cell proliferation of OC3-I5 cells is more responsive to IL-8 treatment compared to the other two cell lines. The IL-8-enhanced proliferation in part regulated by PI3K-AKT and MEK-ERK1/2 pathways. In contrast, IL-8 treatment did not affect cell migration. Together, findings from this thesis suggest that OC3-I5 cells expressed higher levels of IL-8Rs and are more responsive to IL-8 stimulation which may in turn contribute to increased tumorigenesis of OC3-I5 cells.

Abstract I
摘要 II
誌謝 III
Index V
Abbreviations VIII
Introduction 1
Materials and Methods 10
Antibodies and reagents 10
Cell lines and culture 11
Total RNA extraction 12
Reverse transcription polymerase chain reaction (RT-PCR) 12
Semi-quantitative real-time polymerase chain reaction (Q-PCR) 13
Preparation of cell lysate and determination of protein concentration 14
Immunoblotting 15
Trypan blue-based proliferation assay 15
Wound healing assay 16
Statistical analysis 16
Results 17
The mRNA expression levels of IL-8Rsare higher in OC3-I5 cells 17
IL-8-enhanced proliferation of OC3-I5 cells in a dose-dependent manner. 18
IL-8 does not affect cell migration of OC3 cell lines 19
IL-8 induces the activation of MEK-ERK1/2 and PI3K-AKT pathways in OC3 cell lines 19
IL-8 induces phosphorylation of JAK2 but not STAT3 in OC3-I5 cells 20
Inhibiting MEK-ERK1/2 or PI3K-AKT pathway decreases IL-8-enhanced proliferation of OC3-I5 cells 21
IL-8 increases the expression of c-myc, Ets-1 and ATF-2 proto-oncogenes in OC3-I5 cells 22
Discussion 25
Figures 30
Figure 1. The gene expression of cytokines in OC3 cell lines 30
Figure 2. The gene expression of cytokine receptors in OC3 cell lines 31
Figure 3. IL-8 promotes proliferation of OC3-I5 cells 33
Figure 4. IL-8 enhances cell proliferation in a dose-dependent manner 34
Figure 5. IL-8 does not increase migration of OC3 cell lines 37
Figure 6. Conditions for IL-8 treatment 38
Figure 7. IL-8 induces phosphorylation of ERK1/2 in OC3 cell lines 39
Figure 8. IL-8 induces phosphorylation of AKT in OC3 cell lines 41
Figure 9. IL-8 induces phosphorylation of JAK2 in OC3-I5 cells 42
Figure 10. The effect of IL-8 on the phosphorylation of STAT3 43
Figure 11. Inhibitor U0126 reduces the IL-8-enhanced proliferation in OC3 cell lines 45
Figure 12. Inhibitor LY294002 reduces the IL-8-enhanced proliferation in OC3 cell lines 46
Figure 13. The effect of IL-8 on the expression of proliferation-related proto-oncogenes in OC3 cell lines 47
Figure 14. The effect of IL-8 on the expression of cell cycle-related genes in OC3 cell lines 49
Figure 15. Working model 51
Appendix 52
Figure A1. IL-1and TNF induce the phosphorylation of ERK1/2 53
Figure A2. The morphology of OC3 cell lines pretreated with inhibitors U0126 and LY294002 55
Figure A3. The effect of IL-8 on the expression of EMT-related genes in OC3 cell lines 56
Figure A4. Histone modifications in OC3 cell lines 58
Figure A5. The mRNA expression level of IL-8 by Q-PCR 59
Table 60
Table 1. Reverse transcription buffer component 60
Table 2. Reaction temperature and time of reverse transcription 61
Table 3. Sequences of the RT-PCR primers used in this thesis 62
Table 4. Reaction temperature and time of PCR 64
Table 5. Reaction temperature and time of Q-PCR 65
Reference 66

1. Landis, S. H., Murray, T., Bolden, S., and Wingo, P. A. (1998) Cancer statistics, 1998. CA: a cancer journal for clinicians 48, 6-29
2. Silverman, S., Jr., and Bahl, S. (1997) Oral lichen planus update: clinical characteristics, treatment responses, and malignant transformation. American journal of dentistry 10, 259-263
3. Rhodus, N. L., Ho, V., Miller, C. S., Myers, S., and Ondrey, F. (2005) NF-kappaB dependent cytokine levels in saliva of patients with oral preneoplastic lesions and oral squamous cell carcinoma. Cancer detection and prevention 29, 42-45
4. M, E., A, R., G, H., PJ, M., and PA, B. (2005) Quality of dying in head and neck cancer patients: a retrospective analysis of potential indicators of care. Oral Med Oral Pathol Oral Radiol Endod. 100, 147-152
5. A, M., and A, S. (1995) Early diagnosis of asymptomatic oral and oropharyngeal squamous cancers. CA Cancer J Clin 45, 328-351
6. Shafique, K., Mirza, S. S., Vart, P., Memon, A. R., Arain, M. I., Tareen, M. F., and Haq, Z. U. (2012) Areca nut chewing and systemic inflammation: evidence of a common pathway for systemic diseases. Journal of inflammation 9, 22
7. Bistrian, B. (2007) Systemic response to inflammation. Nutrition reviews 65, S170-172
8. SJ, M., and AC, S. (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132, 598-611
9. C, R. (2006) Leukocytes, inflammation, and angiogenesis in cancer: fatal attractions. J Leukoc Biol 80, 682-684
10. F, S., C, Z., X, W., L, Y., and N, F. (2008) Role of myeloid cells in tumor angiogenesis and growth. Trends Cell Biol 18, 372-378
11. Gregory, A. D., and Houghton, A. M. (2011) Tumor-Associated Neutrophils: New Targets for Cancer Therapy. Cancer Research 71, 2411-2416
12. CA, D., MJ, K., and MC, P. (1990) The Physiological and Pathological Effects of Cytokines. New York: Liss
13. A, M., T, K., N, H., T, Y., and K, A. (1992) Cytokine receptors and signal transduction. Annu Rev Immunol 10, 295-331
14. Li, A., Dubey, S., Varney, M. L., Dave, B. J., and Singh, R. K. (2003) IL-8 Directly Enhanced Endothelial Cell Survival, Proliferation, and Matrix Metalloproteinases Production and Regulated Angiogenesis. The Journal of Immunology 170, 3369-3376
15. Dranoff, G. (2004) Cytokines in cancer pathogenesis and cancer therapy. Nature Reviews Cancer 4, 11-22
16. Waugh, D. J. J., and Wilson, C. (2008) The Interleukin-8 Pathway in Cancer. Clin Cancer Res 14, 6735-6741
17. Chen, M.-F., Lu, M.-S., Chen, P.-T., Chen, W.-C., Lin, P.-Y., and Lee, K.-D. (2012) Role of interleukin 1 beta in esophageal squamous cell carcinoma. J Mol Med (Berl) 1, 89-100
18. Liao, D., Luo, Y., Markowitz, D., Xiang, R., and Reisfeld, R. A. (2009) Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PloS one 4, e7965
19. Balkwill, F., Charles, K. A., and Mantovani, A. (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer cell 7, 211-217
20. CA, D. (2006) The paradox of pro-inflammatory cytokines in cancer. Cancer Metastasis Rev 25, 307-313
21. Jablonska, E., Piotrowski, L., and Grabowska, Z. (1997) Serum Levels of IL-1b, IL-6, TNF-a, sTNF-RI and CRP in Patients with Oral Cavity Cancer. Pathology oncology research : POR 3, 126-129
22. SahebJamee, M., Eslami, M., AtarbashiMoghadam, F., and Sarafnejad, A. (2008) Salivary concentration of TNFalpha, IL1 alpha, IL6, and IL8 in oral squamous cell carcinoma. Medicina oral, patologia oral y cirugia bucal 13, E292-295
23. Wang, L., Zhao, Y., Liu, Y., Akiyama, K., Chen, C., Qu, C., Jin, Y., and Shi, S. (2013) IFN-gamma and TNF-alpha Synergistically Induce Mesenchymal Stem Cell Impairment and Tumorigenesis via NFkappaB Signaling. Stem cells
24. Lewis, A. M., Varghese, S., Xu, H., and Alexander, H. R. (2006) Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment. Journal of translational medicine 4, 48
25. Apte, R. N., Dotan, S., Elkabets, M., White, M. R., Reich, E., Carmi, Y., Song, X., Dvozkin, T., Krelin, Y., and Voronov, E. (2006) The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions. Cancer Metastasis Rev 25, 387-408
26. Seruga, B., Zhang, H., Bernstein, L. J., and Tannock, I. F. (2008) Cytokines and their relationship to the symptoms and outcome of cancer. Nature reviews. Cancer 8, 887-899
27. Xie, K. (2001) Interleukin-8 and human cancer biology. Cytokine & growth factor reviews 12, 375-391
28. Smith, D. R., Polverini, P. J., Kunkel, S. L., Orringer, M. B., Whyte, R. I., Burdick, M. D., Wilke, C. A., and Strieter, R. M. (1994) Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma. The Journal of experimental medicine 179, 1409-1415
29. Arenberg, D. A., Kunkel, S. L., Polverini, P. J., Glass, M., Burdick, M. D., and Strieter, R. M. (1996) Inhibition of interleukin-8 reduces tumorigenesis of human non-small cell lung cancer in SCID mice. The Journal of clinical investigation 97, 2792-2802
30. Brew, R., Southern, S. A., Flanagan, B. F., McDicken, I. W., and Christmas, S. E. (1996) Detection of interleukin-8 mRNA and protein in human colorectal carcinoma cells. European journal of cancer 32A, 2142-2147
31. Yoneda, J., Kuniyasu, H., Crispens, M. A., Price, J. E., Bucana, C. D., and Fidler, I. J. (1998) Expression of angiogenesis-related genes and progression of human ovarian carcinomas in nude mice. Journal of the National Cancer Institute 90, 447-454
32. Miller, L. J., Kurtzman, S. H., Wang, Y., Anderson, K. H., Lindquist, R. R., and Kreutzer, D. L. (1998) Expression of interleukin-8 receptors on tumor cells and vascular endothelial cells in human breast cancer tissue. Anticancer research 18, 77-81
33. Singh, R. K., Gutman, M., Radinsky, R., Bucana, C. D., and Fidler, I. J. (1994) Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res 54, 3242-3247
34. Greene, G. F., Kitadai, Y., Pettaway, C. A., von Eschenbach, A. C., Bucana, C. D., and Fidler, I. J. (1997) Correlation of metastasis-related gene expression with metastatic potential in human prostate carcinoma cells implanted in nude mice using an in situ messenger RNA hybridization technique. Am J Pathol 150, 1571-1582
35. Kitadai, Y., Haruma, K., Sumii, K., Yamamoto, S., Ue, T., Yokozaki, H., Yasui, W., Ohmoto, Y., Kajiyama, G., Fidler, I. J., and Tahara, E. (1998) Expression of interleukin-8 correlates with vascularity in human gastric carcinomas. Am J Pathol 152, 93-100
36. Schadendorf, D., Moller, A., Algermissen, B., Worm, M., Sticherling, M., and Czarnetzki, B. M. (1993) IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J Immunol 151, 2667-2675
37. Galffy, G., Mohammed, K. A., Dowling, P. A., Nasreen, N., Ward, M. J., and Antony, V. B. (1999) Interleukin 8: an autocrine growth factor for malignant mesothelioma. Cancer Res 59, 367-371
38. Norgauer, J., Metzner, B., and Schraufstatter, I. (1996) Expression and growth-promoting function of the IL-8 receptor beta in human melanoma cells. J Immunol 156, 1132-1137
39. Yamanaka, R., Tanaka, R., Yoshida, S., Saitoh, T., and Fujita, K. (1995) Growth inhibition of human glioma cells modulated by retrovirus gene transfection with antisense IL-8. Journal of neuro-oncology 25, 59-65
40. Benoy, I. H., Salgado, R., Van Dam, P., Geboers, K., Van Marck, E., Scharpe, S., Vermeulen, P. B., and Dirix, L. Y. (2004) Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clin Cancer Res 10, 7157-7162
41. Lehrer, S., Diamond, E. J., Mamkine, B., Stone, N. N., and Stock, R. G. (2004) Serum interleukin-8 is elevated in men with prostate cancer and bone metastases. Technology in cancer research & treatment 3, 411
42. Wigmore, S. J., Fearon, K. C., Sangster, K., Maingay, J. P., Garden, O. J., and Ross, J. A. (2002) Cytokine regulation of constitutive production of interleukin-8 and -6 by human pancreatic cancer cell lines and serum cytokine concentrations in patients with pancreatic cancer. International journal of oncology 21, 881-886
43. Freund, A., Chauveau, C., Brouillet, J. P., Lucas, A., Lacroix, M., Licznar, A., Vignon, F., and Lazennec, G. (2003) IL-8 expression and its possible relationship with estrogen-receptor-negative status of breast cancer cells. Oncogene 22, 256-265
44. Ning, Y., Manegold, P. C., Hong, Y. K., Zhang, W., Pohl, A., Lurje, G., Winder, T., Yang, D., LaBonte, M. J., Wilson, P. M., Ladner, R. D., and Lenz, H. J. (2011) Interleukin-8 is associated with proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models. International journal of cancer. Journal international du cancer 128, 2038-2049
45. Karashima, T., Sweeney, P., Kamat, A., Huang, S., Kim, S. J., Bar-Eli, M., McConkey, D. J., and Dinney, C. P. (2003) Nuclear factor-kappaB mediates angiogenesis and metastasis of human bladder cancer through the regulation of interleukin-8. Clin Cancer Res 9, 2786-2797
46. Knall, C., Worthen, G. S., and Johnson, G. L. (1997) Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Proceedings of the National Academy of Sciences of the United States of America 94, 3052-3057
47. Baker, S. J., Rane, S. G., and Reddy, E. P. (2007) Hematopoietic cytokine receptor signaling. Oncogene 26, 6724-6737
48. Kim, M. J., Nam, H. J., Kim, H. P., Han, S. W., Im, S. A., Kim, T. Y., Oh, D. Y., and Bang, Y. J. (2013) OPB-31121, a novel small molecular inhibitor, disrupts the JAK2/STAT3 pathway and exhibits an antitumor activity in gastric cancer cells. Cancer letters 335, 145-152
49. T, M. (1998) The Molecular Biology of Cytokines. John Wiley & Sons
50. Cheng, G. Z., Park, S., Shu, S., He, L., Kong, W., Zhang, W., Yuan, Z., Wang, L. H., and Cheng, J. Q. (2008) Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery. Current cancer drug targets 8, 2-6
51. Tang, J. M., He, Q. Y., Guo, R. X., and Chang, X. J. (2006) Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung cancer 51, 181-191
52. Le Page, C., Koumakpayi, I. H., Alam-Fahmy, M., Mes-Masson, A. M., and Saad, F. (2006) Expression and localisation of Akt-1, Akt-2 and Akt-3 correlate with clinical outcome of prostate cancer patients. British journal of cancer 94, 1906-1912
53. Lee, C. Y., Huang, C. Y., Chen, M. Y., Lin, C. Y., Hsu, H. C., and Tang, C. H. (2011) IL-8 increases integrin expression and cell motility in human chondrosarcoma cells. Journal of cellular biochemistry 112, 2549-2557
54. Zhang, Y., Wang, L., Zhang, M., Jin, M., Bai, C., and Wang, X. (2012) Potential mechanism of interleukin-8 production from lung cancer cells: an involvement of EGF-EGFR-PI3K-Akt-Erk pathway. Journal of cellular physiology 227, 35-43
55. Oudin, S., and Pugin, J. (2002) Role of MAP kinase activation in interleukin-8 production by human BEAS-2B bronchial epithelial cells submitted to cyclic stretch. American journal of respiratory cell and molecular biology 27, 107-114
56. Brott, B. K., Alessandrini, A., Largaespada, D. A., Copeland, N. G., Jenkins, N. A., Crews, C. M., and Erikson, R. L. (1993) MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 4, 921-929
57. Touyz, R. M., and Schiffrin, E. L. (2000) Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacological reviews 52, 639-672
58. Eguchi, S., Numaguchi, K., Iwasaki, H., Matsumoto, T., Yamakawa, T., Utsunomiya, H., Motley, E. D., Kawakatsu, H., Owada, K. M., Hirata, Y., Marumo, F., and Inagami, T. (1998) Calcium-dependent epidermal growth factor receptor transactivation mediates the angiotensin II-induced mitogen-activated protein kinase activation in vascular smooth muscle cells. The Journal of biological chemistry 273, 8890-8896
59. Knall, C., Young, S., Nick, J. A., Buhl, A. M., Worthen, G. S., and Johnson, G. L. (1996) Interleukin-8 regulation of the Ras/Raf/mitogen-activated protein kinase pathway in human neutrophils. The Journal of biological chemistry 271, 2832-2838
60. Luppi, F., Longo, A. M., de Boer, W. I., Rabe, K. F., and Hiemstra, P. S. (2007) Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation. Lung cancer 56, 25-33
61. Venkatakrishnan, G., Salgia, R., and Groopman, J. E. (2000) Chemokine receptors CXCR-1/2 activate mitogen-activated protein kinase via the epidermal growth factor receptor in ovarian cancer cells. The Journal of biological chemistry 275, 6868-6875
62. Glynn, P. C., Henney, E., and Hall, I. P. (2002) The selective CXCR2 antagonist SB272844 blocks interleukin-8 and growth-related oncogene-alpha-mediated inhibition of spontaneous neutrophil apoptosis. Pulmonary pharmacology & therapeutics 15, 103-110
63. Nguyen, T. K., Jordan, N., Friedberg, J., Fisher, R. I., Dent, P., and Grant, S. (2010) Inhibition of MEK/ERK1/2 sensitizes lymphoma cells to sorafenib-induced apoptosis. Leukemia research 34, 379-386
64. Murphy, C., McGurk, M., Pettigrew, J., Santinelli, A., Mazzucchelli, R., Johnston, P. G., Montironi, R., and Waugh, D. J. (2005) Nonapical and cytoplasmic expression of interleukin-8, CXCR1, and CXCR2 correlates with cell proliferation and microvessel density in prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 11, 4117-4127
65. Takami, M., Terry, V., and Petruzzelli, L. (2002) Signaling pathways involved in IL-8-dependent activation of adhesion through Mac-1. J Immunol 168, 4559-4566
66. Nasser, M. W., Marjoram, R. J., Brown, S. L., and Richardson, R. M. (2005) Cross-desensitization among CXCR1, CXCR2, and CCR5: role of protein kinase C-epsilon. J Immunol 174, 6927-6933
67. Rajagopalan, L., and Rajarathnam, K. (2004) Ligand selectivity and affinity of chemokine receptor CXCR1. Role of N-terminal domain. The Journal of biological chemistry 279, 30000-30008
68. Doucet, C., Brouty-Boye, D., Pottin-Clemenceau, C., Jasmin, C., Canonica, G. W., and Azzarone, B. (1998) IL-4 and IL-13 specifically increase adhesion molecule and inflammatory cytokine expression in human lung fibroblasts. International immunology 10, 1421-1433
69. Weinstein, I. B., and Joe, A. K. (2006) Mechanisms of disease: Oncogene addiction--a rationale for molecular targeting in cancer therapy. Nature clinical practice. Oncology 3, 448-457
70. Pavelic, K., Pecina Slaus, N., and Spaventi, R. (1991) Growth factors and proto-oncogenes in early mouse embryogenesis and tumorigenesis. The International journal of developmental biology 35, 209-214
71. Lincoln, D. W., 2nd, and Bove, K. (2005) The transcription factor Ets-1 in breast cancer. Frontiers in bioscience : a journal and virtual library 10, 506-511
72. Furlan, A., Vercamer, C., Desbiens, X., and Pourtier, A. (2008) Ets-1 triggers and orchestrates the malignant phenotype of mammary cancer cells within their matrix environment. Journal of cellular physiology 215, 782-793
73. Hahne, J. C., Okuducu, A. F., Kaminski, A., Florin, A., Soncin, F., and Wernert, N. (2005) Ets-1 expression promotes epithelial cell transformation by inducing migration, invasion and anchorage-independent growth. Oncogene 24, 5384-5388
74. Dittmer, J. (2003) The biology of the Ets1 proto-oncogene. Molecular cancer 2, 29
75. Seth, A., and Papas, T. S. (1990) The c-ets-1 proto-oncogene has oncogenic activity and is positively autoregulated. Oncogene 5, 1761-1767
76. Adhikary, S., and Eilers, M. (2005) Transcriptional regulation and transformation by Myc proteins. Nature reviews. Molecular cell biology 6, 635-645
77. Coller, H. A., Grandori, C., Tamayo, P., Colbert, T., Lander, E. S., Eisenman, R. N., and Golub, T. R. (2000) Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. Proceedings of the National Academy of Sciences of the United States of America 97, 3260-3265
78. Mukherjee, S., and Conrad, S. E. (2005) c-Myc suppresses p21WAF1/CIP1 expression during estrogen signaling and antiestrogen resistance in human breast cancer cells. The Journal of biological chemistry 280, 17617-17625
79. Baldin, V., Lukas, J., Marcote, M. J., Pagano, M., and Draetta, G. (1993) Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes & development 7, 812-821
80. van de Putte, G., Holm, R., Lie, A. K., Trope, C. G., and Kristensen, G. B. (2003) Expression of p27, p21, and p16 protein in early squamous cervical cancer and its relation to prognosis. Gynecologic oncology 89, 140-147
81. Vlahopoulos, S. A., Logotheti, S., Mikas, D., Giarika, A., Gorgoulis, V., and Zoumpourlis, V. (2008) The role of ATF-2 in oncogenesis. BioEssays : news and reviews in molecular, cellular and developmental biology 30, 314-327
82. Takasawa, S., Ikeda, T., Akiyama, T., Nata, K., Nakagawa, K., Shervani, N. J., Noguchi, N., Murakami-Kawaguchi, S., Yamauchi, A., Takahashi, I., Tomioka-Kumagai, T., and Okamoto, H. (2006) Cyclin D1 activation through ATF-2 in Reg-induced pancreatic beta-cell regeneration. FEBS letters 580, 585-591
83. Lin, S. C., Liu, C. J., Chiu, C. P., Chang, S. M., Lu, S. Y., and Chen, Y. J. (2004) Establishment of OC3 oral carcinoma cell line and identification of NF-kappa B activation responses to areca nut extract. J Oral Pathol Med 33, 79-86
84. Quentmeier, H., Schumann-Kindel, G., Muhlradt, P. F., and Drexler, H. G. (1994) Induction of proto-oncogene and cytokine expression in human peripheral blood monocytes and the monocytic cell line THP-1 after stimulation with mycoplasma-derived material MDHM. Leukemia research 18, 319-325
85. Fitzpatrick, D. R., Peroni, D. J., and Bielefeldt-Ohmann, H. (1995) The role of growth factors and cytokines in the tumorigenesis and immunobiology of malignant mesothelioma. American journal of respiratory cell and molecular biology 12, 455-460
86. Ravi, A., Gurtan, A. M., Kumar, M. S., Bhutkar, A., Chin, C., Lu, V., Lees, J. A., Jacks, T., and Sharp, P. A. (2012) Proliferation and tumorigenesis of a murine sarcoma cell line in the absence of DICER1. Cancer cell 21, 848-855
87. Stengel, K., and Zheng, Y. (2011) Cdc42 in oncogenic transformation, invasion, and tumorigenesis. Cellular signalling 23, 1415-1423
88. Sandi, M. J., Hamidi, T., Malicet, C., Cano, C., Loncle, C., Pierres, A., Dagorn, J. C., and Iovanna, J. L. (2011) p8 expression controls pancreatic cancer cell migration, invasion, adhesion, and tumorigenesis. Journal of cellular physiology 226, 3442-3451
89. Cakir, M., and Grossman, A. B. (2009) Targeting MAPK (Ras/ERK) and PI3K/Akt pathways in pituitary tumorigenesis. Expert opinion on therapeutic targets 13, 1121-1134
90. Li, H., Cai, X., Fan, X., Moquin, B., Stoicov, C., and Houghton, J. (2008) Fas Ag-FasL coupling leads to ERK1/2-mediated proliferation of gastric mucosal cells. American journal of physiology. Gastrointestinal and liver physiology 294, G263-275
91. Luo, J., Manning, B. D., and Cantley, L. C. (2003) Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer cell 4, 257-262
92. Chang, F., Lee, J. T., Navolanic, P. M., Steelman, L. S., Shelton, J. G., Blalock, W. L., Franklin, R. A., and McCubrey, J. A. (2003) Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia 17, 590-603
93. Rawlings, J. S., Rosler, K. M., and Harrison, D. A. (2004) The JAK/STAT signaling pathway. Journal of cell science 117, 1281-1283
94. Ruchatz, H., Coluccia, A. M., Stano, P., Marchesi, E., and Gambacorti-Passerini, C. (2003) Constitutive activation of Jak2 contributes to proliferation and resistance to apoptosis in NPM/ALK-transformed cells. Experimental hematology 31, 309-315
95. Liu, C. B., Itoh, T., Arai, K., and Watanabe, S. (1999) Constitutive activation of JAK2 confers murine interleukin-3-independent survival and proliferation of BA/F3 cells. The Journal of biological chemistry 274, 6342-6349
96. Ihle, J. N., and Kerr, I. M. (1995) Jaks and Stats in signaling by the cytokine receptor superfamily. Trends in genetics : TIG 11, 69-74
97. Ihle, J. N., Nosaka, T., Thierfelder, W., Quelle, F. W., and Shimoda, K. (1997) Jaks and Stats in cytokine signaling. Stem cells 15 Suppl 1, 105-111; discussion 112
98. Chen, E., Gadina, M., Chen, M., and O'Shea, J. J. (1999) Advances in cytokine signaling: the role of Jaks and STATs. Transplantation proceedings 31, 1482-1487
99. Lang, K., Niggemann, B., Zanker, K. S., and Entschladen, F. (2002) Signal processing in migrating T24 human bladder carcinoma cells: role of the autocrine interleukin-8 loop. International journal of cancer. Journal international du cancer 99, 673-680
100. Adamson, E. D. (1987) Oncogenes in development. Development 99, 449-471
101. Switzer, C. H., Cheng, R. Y., Ridnour, L. A., Glynn, S. A., Ambs, S., and Wink, D. A. (2012) Ets-1 is a transcriptional mediator of oncogenic nitric oxide signaling in estrogen receptor-negative breast cancer. Breast cancer research : BCR 14, R125
102. Dalla-Favera, R., Gelmann, E. P., Martinotti, S., Franchini, G., Papas, T. S., Gallo, R. C., and Wong-Staal, F. (1982) Cloning and characterization of different human sequences related to the onc gene (v-myc) of avian myelocytomatosis virus (MC29). Proceedings of the National Academy of Sciences of the United States of America 79, 6497-6501
103. Rochlitz, C. F., Herrmann, R., and de Kant, E. (1996) Overexpression and amplification of c-myc during progression of human colorectal cancer. Oncology 53, 448-454
104. McNeil, C. M., Sergio, C. M., Anderson, L. R., Inman, C. K., Eggleton, S. A., Murphy, N. C., Millar, E. K., Crea, P., Kench, J. G., Alles, M. C., Gardiner-Garden, M., Ormandy, C. J., Butt, A. J., Henshall, S. M., Musgrove, E. A., and Sutherland, R. L. (2006) c-Myc overexpression and endocrine resistance in breast cancer. The Journal of steroid biochemistry and molecular biology 102, 147-155
105. Miller, D. M., Thomas, S. D., Islam, A., Muench, D., and Sedoris, K. (2012) c-Myc and cancer metabolism. Clin Cancer Res 18, 5546-5553
106. Stearns, D., Chaudhry, A., Abel, T. W., Burger, P. C., Dang, C. V., and Eberhart, C. G. (2006) c-myc overexpression causes anaplasia in medulloblastoma. Cancer Res 66, 673-681
107. Biswas, D. K., Shi, Q., Baily, S., Strickland, I., Ghosh, S., Pardee, A. B., and Iglehart, J. D. (2004) NF-kappa B activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proceedings of the National Academy of Sciences of the United States of America 101, 10137-10142
108. Coqueret, O. (2003) New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol 13, 65-70
109. Courtney, K. D., Corcoran, R. B., and Engelman, J. A. (2010) The PI3K pathway as drug target in human cancer. J Clin Oncol 28, 1075-1083
110. Molinolo, A. A., Amornphimoltham, P., Squarize, C. H., Castilho, R. M., Patel, V., and Gutkind, J. S. (2009) Dysregulated molecular networks in head and neck carcinogenesis. Oral oncology 45, 324-334
111. Chang, F., Steelman, L. S., Lee, J. T., Shelton, J. G., Navolanic, P. M., Blalock, W. L., Franklin, R. A., and McCubrey, J. A. (2003) Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 17, 1263-1293
112. Heim, M. H. (1999) The Jak-STAT pathway: cytokine signalling from the receptor to the nucleus. Journal of receptor and signal transduction research 19, 75-120
113. Verma, A., Kambhampati, S., Parmar, S., and Platanias, L. C. (2003) Jak family of kinases in cancer. Cancer Metastasis Rev 22, 423-434
114. Leonard, W. J., and O'Shea, J. J. (1998) Jaks and STATs: biological implications. Annu Rev Immunol 16, 293-322
115. Raghuwanshi, S. K., Su, Y., Singh, V., Haynes, K., Richmond, A., and Richardson, R. M. (2012) The chemokine receptors CXCR1 and CXCR2 couple to distinct G protein-coupled receptor kinases to mediate and regulate leukocyte functions. J Immunol 189, 2824-2832
116. Krupnick, J. G., and Benovic, J. L. (1998) The role of receptor kinases and arrestins in G protein-coupled receptor regulation. Annual review of pharmacology and toxicology 38, 289-319
117. Gravdal, K., Halvorsen, O. J., Haukaas, S. A., and Akslen, L. A. (2007) A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 13, 7003-7011
118. Ren, G., Baritaki, S., Marathe, H., Feng, J., Park, S., Beach, S., Bazeley, P. S., Beshir, A. B., Fenteany, G., Mehra, R., Daignault, S., Al-Mulla, F., Keller, E., Bonavida, B., de la Serna, I., and Yeung, K. C. (2012) Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res 72, 3091-3104
119. Sawan, C., and Herceg, Z. (2010) Histone modifications and cancer. Advances in genetics 70, 57-85
120. Li, F., Martienssen, R., and Cande, W. Z. (2011) Coordination of DNA replication and histone modification by the Rik1-Dos2 complex. Nature 475, 244-248
121. Sahin, A., Velten, M., Pietsch, T., Knuefermann, P., Okuducu, A. F., Hahne, J. C., and Wernert, N. (2005) Inactivation of Ets 1 transcription factor by a specific decoy strategy reduces rat C6 glioma cell proliferation and mmp-9 expression. International journal of molecular medicine 15, 771-776
122. Holterman, C. E., Franovic, A., Payette, J., and Lee, S. (2010) ETS-1 oncogenic activity mediated by transforming growth factor alpha. Cancer Res 70, 730-740
123. Ricote, M., Garcia-Tunon, I., Bethencourt, F., Fraile, B., Onsurbe, P., Paniagua, R., and Royuela, M. (2006) The p38 transduction pathway in prostatic neoplasia. The Journal of pathology 208, 401-407
124. Dang, C. V. (1999) c-Myc target genes involved in cell growth, apoptosis, and metabolism. Molecular and cellular biology 19, 1-11
125. Gordan, J. D., Bertout, J. A., Hu, C. J., Diehl, J. A., and Simon, M. C. (2007) HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer cell 11, 335-347
126. Jansen-Durr, P., Meichle, A., Steiner, P., Pagano, M., Finke, K., Botz, J., Wessbecher, J., Draetta, G., and Eilers, M. (1993) Differential modulation of cyclin gene expression by MYC. Proceedings of the National Academy of Sciences of the United States of America 90, 3685-3689
127. Berns, K., Hijmans, E. M., and Bernards, R. (1997) Repression of c-Myc responsive genes in cycling cells causes G1 arrest through reduction of cyclin E/CDK2 kinase activity. Oncogene 15, 1347-1356