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  1. NTU Theses and Dissertations Repository
  2. 醫學院
  3. 牙醫專業學院
  4. 口腔生物科學研究所
請用此 Handle URI 來引用此文件: http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22431
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dc.contributor.advisor張正琪(Cheng-Chi Chang)
dc.contributor.authorChih-Hao Changen
dc.contributor.author張致皓zh_TW
dc.date.accessioned2021-06-08T04:17:39Z-
dc.date.copyright2010-09-09
dc.date.issued2010
dc.date.submitted2010-07-29
dc.identifier.citation1. Vokes EE, Weichselbaum RR, Lippman SM, Hong WK. Head and neck cancer. N Engl J Med 1993; 328: 184-94.
2. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med 2008; 359: 1143-54.
3. el-Naggar AK, Hurr K, Luna MA, Goepfert H, Hong WK, Batsakis JG. Intratumoral genetic heterogeneity in primary head and neck squamous carcinoma using microsatellite markers. Diagn Mol Pathol 1997; 6: 305-8.
4. Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med 2001; 345: 1890-900.
5. Liao CT, Chang JT, Wang HM, et al. Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol 2008; 15: 915-22.
6. O'Brien TP, Yang GP, Sanders L, Lau LF. Expression of cyr61, a growth factor-inducible immediate-early gene. Mol Cell Biol 1990; 10: 3569-77.
7. Joliot V, Martinerie C, Dambrine G, et al. Proviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas. Mol Cell Biol 1992; 12: 10-21.
8. Pennica D, Swanson TA, Welsh JW, et al. WISP genes are members of the connective tissue growth factor family that are up-regulated in wnt-1-transformed cells and aberrantly expressed in human colon tumors. Proc Natl Acad Sci U S A 1998; 95: 14717-22.
9. Bork P. The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett 1993; 327: 125-30.
10. Kireeva ML, Mo FE, Yang GP, Lau LF. Cyr61, a product of a growth factor-inducible immediate-early gene, promotes cell proliferation, migration, and adhesion. Mol Cell Biol 1996; 16: 1326-34.
11. Dean RA, Butler GS, Hamma-Kourbali Y, et al. Identification of candidate angiogenic inhibitors processed by matrix metalloproteinase 2 (MMP-2) in cell-based proteomic screens: disruption of vascular endothelial growth factor (VEGF)/heparin affin regulatory peptide (pleiotrophin) and VEGF/Connective tissue growth factor angiogenic inhibitory complexes by MMP-2 proteolysis. Mol Cell Biol 2007; 27: 8454-65.
12. Lau LF, Lam SC. The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res 1999; 248: 44-57.
13. Perbal B, Brigstock DR, Lau LF. Report on the second international workshop on the CCN family of genes. Mol Pathol 2003; 56: 80-5.
14. Ristimaki A, Honkanen N, Jankala H, Sipponen P, Harkonen M. Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res 1997; 57: 1276-80.
15. Brigstock DR. The connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev 1999; 20: 189-206.
16. Uefuji K, Ichikura T, Mochizuki H. Expression of cyclooxygenase-2 in human gastric adenomas and adenocarcinomas. J Surg Oncol 2001; 76: 26-30.
17. Tong X, Xie D, O'Kelly J, Miller CW, Muller-Tidow C, Koeffler HP. Cyr61, a member of CCN family, is a tumor suppressor in non-small cell lung cancer. J Biol Chem 2001; 276: 47709-14.
18. Soon LL, Yie TA, Shvarts A, Levine AJ, Su F, Tchou-Wong KM. Overexpression of WISP-1 down-regulated motility and invasion of lung cancer cells through inhibition of Rac activation. J Biol Chem 2003; 278: 11465-70.
19. Hashimoto Y, Shindo-Okada N, Tani M, et al. Expression of the Elm1 gene, a novel gene of the CCN (connective tissue growth factor, Cyr61/Cef10, and neuroblastoma overexpressed gene) family, suppresses In vivo tumor growth and metastasis of K-1735 murine melanoma cells. J Exp Med 1998; 187: 289-96.
20. Chen CC, Chen N, Lau LF. The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts. J Biol Chem 2001; 276: 10443-52.
21. Ball DK, Rachfal AW, Kemper SA, Brigstock DR. The heparin-binding 10 kDa fragment of connective tissue growth factor (CTGF) containing module 4 alone stimulates cell adhesion. J Endocrinol 2003; 176: R1-7.
22. Brigstock DR, Steffen CL, Kim GY, Vegunta RK, Diehl JR, Harding PA. Purification and characterization of novel heparin-binding growth factors in uterine secretory fluids. Identification as heparin-regulated Mr 10,000 forms of connective tissue growth factor. J Biol Chem 1997; 272: 20275-82.
23. Denton CP, Abraham DJ. Transforming growth factor-beta and connective tissue growth factor: key cytokines in scleroderma pathogenesis. Curr Opin Rheumatol 2001; 13: 505-11.
24. Hishikawa K, Oemar BS, Tanner FC, Nakaki T, Luscher TF, Fujii T. Connective tissue growth factor induces apoptosis in human breast cancer cell line MCF-7. J Biol Chem 1999; 274: 37461-6.
25. Babic AM, Chen CC, Lau LF. Fisp12/mouse connective tissue growth factor mediates endothelial cell adhesion and migration through integrin alphavbeta3, promotes endothelial cell survival, and induces angiogenesis in vivo. Mol Cell Biol 1999; 19: 2958-66.
26. Nakanishi T, Nishida T, Shimo T, et al. Effects of CTGF/Hcs24, a product of a hypertrophic chondrocyte-specific gene, on the proliferation and differentiation of chondrocytes in culture. Endocrinology 2000; 141: 264-73.
27. Yosimichi G, Nakanishi T, Nishida T, Hattori T, Takano-Yamamoto T, Takigawa M. CTGF/Hcs24 induces chondrocyte differentiation through a p38 mitogen-activated protein kinase (p38MAPK), and proliferation through a p44/42 MAPK/extracellular-signal regulated kinase (ERK). Eur J Biochem 2001; 268: 6058-65.
28. Perbal B. The CCN family of genes: a brief history. Mol Pathol 2001; 54: 103-4.
29. Perbal B. NOV (nephroblastoma overexpressed) and the CCN family of genes: structural and functional issues. Mol Pathol 2001; 54: 57-79.
30. Planque N, Perbal B. A structural approach to the role of CCN (CYR61/CTGF/NOV) proteins in tumourigenesis. Cancer Cell Int 2003; 3: 15.
31. Kang Y, Siegel PM, Shu W, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 2003; 3: 537-49.
32. Shimo T, Kubota S, Yoshioka N, et al. Pathogenic role of connective tissue growth factor (CTGF/CCN2) in osteolytic metastasis of breast cancer. J Bone Miner Res 2006; 21: 1045-59.
33. Wong YF, Cheung TH, Tsao GS, et al. Genome-wide gene expression profiling of cervical cancer in Hong Kong women by oligonucleotide microarray. Int J Cancer 2006; 118: 2461-9.
34. Wenger C, Ellenrieder V, Alber B, et al. Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells. Oncogene 1999; 18: 1073-80.
35. Kubo M, Kikuchi K, Nashiro K, et al. Expression of fibrogenic cytokines in desmoplastic malignant melanoma. Br J Dermatol 1998; 139: 192-7.
36. Liu L, Li Z, Feng G, You W, Li J. Expression of connective tissue growth factor is in agreement with the expression of VEGF, VEGF-C, -D and associated with shorter survival in gastric cancer. Pathol Int 2007; 57: 712-8.
37. Xie D, Yin D, Wang HJ, et al. Levels of expression of CYR61 and CTGF are prognostic for tumor progression and survival of individuals with gliomas. Clin Cancer Res 2004; 10: 2072-81.
38. Koliopanos A, Friess H, di Mola FF, et al. Connective tissue growth factor gene expression alters tumor progression in esophageal cancer. World J Surg 2002; 26: 420-7.
39. Zeng ZJ, Yang LY, Ding X, Wang W. Expressions of cysteine-rich61, connective tissue growth factor and Nov genes in hepatocellular carcinoma and their clinical significance. World J Gastroenterol 2004; 10: 3414-8.
40. Dornhofer N, Spong S, Bennewith K, et al. Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis. Cancer Res 2006; 66: 5816-27.
41. Chien W, Yin D, Gui D, et al. Suppression of cell proliferation and signaling transduction by connective tissue growth factor in non-small cell lung cancer cells. Mol Cancer Res 2006; 4: 591-8.
42. Moritani NH, Kubota S, Nishida T, et al. Suppressive effect of overexpressed connective tissue growth factor on tumor cell growth in a human oral squamous cell carcinoma-derived cell line. Cancer Lett 2003; 192: 205-14.
43. Shakunaga T, Ozaki T, Ohara N, et al. Expression of connective tissue growth factor in cartilaginous tumors. Cancer 2000; 89: 1466-73.
44. Karp X, Ambros V. Developmental biology. Encountering microRNAs in cell fate signaling. Science 2005; 310: 1288-9.
45. Xu P, Guo M, Hay BA. MicroRNAs and the regulation of cell death. Trends Genet 2004; 20: 617-24.
46. Miska EA, Alvarez-Saavedra E, Townsend M, et al. Microarray analysis of microRNA expression in the developing mammalian brain. Genome Biol 2004; 5: R68.
47. Voorhoeve PM, le Sage C, Schrier M, et al. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell 2006; 124: 1169-81.
48. Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet 2007; 39: 673-7.
49. Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 2007; 449: 682-8.
50. Lim LP, Lau NC, Garrett-Engele P, et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 2005; 433: 769-73.
51. Chan CS, Elemento O, Tavazoie S. Revealing posttranscriptional regulatory elements through network-level conservation. PLoS Comput Biol 2005; 1: e69.
52. Chu YW, Yang PC, Yang SC, et al. Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol 1997; 17: 353-60.
53. Israel A, Sharan R, Ruppin E, Galun E. Increased microRNA activity in human cancers. PLoS One 2009; 4: e6045.
54. Gironella M, Seux M, Xie MJ, et al. Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development. Proc Natl Acad Sci U S A 2007; 104: 16170-5.
55. Carlsson P, Mahlapuu M. Forkhead transcription factors: key players in development and metabolism. Dev Biol 2002; 250: 1-23.
56. Katoh M. Human FOX gene family (Review). Int J Oncol 2004; 25: 1495-500.
57. Hu H, Wang B, Borde M, et al. Foxp1 is an essential transcriptional regulator of B cell development. Nat Immunol 2006; 7: 819-26.
58. Shu W, Yang H, Zhang L, Lu MM, Morrisey EE. Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors. J Biol Chem 2001; 276: 27488-97.
59. Wang B, Weidenfeld J, Lu MM, et al. Foxp1 regulates cardiac outflow tract, endocardial cushion morphogenesis and myocyte proliferation and maturation. Development 2004; 131: 4477-87.
60. Shi C, Zhang X, Chen Z, et al. Integrin engagement regulates monocyte differentiation through the forkhead transcription factor Foxp1. J Clin Invest 2004; 114: 408-18.
61. Banham AH, Beasley N, Campo E, et al. The FOXP1 winged helix transcription factor is a novel candidate tumor suppressor gene on chromosome 3p. Cancer Res 2001; 61: 8820-9.
62. Banham AH, Connors JM, Brown PJ, et al. Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma. Clin Cancer Res 2005; 11: 1065-72.
63. Barrans SL, Fenton JA, Banham A, Owen RG, Jack AS. Strong expression of FOXP1 identifies a distinct subset of diffuse large B-cell lymphoma (DLBCL) patients with poor outcome. Blood 2004; 104: 2933-5.
64. Smith RJ, Bryant RG. Metal substitutions incarbonic anhydrase: a halide ion probe study. Biochem Biophys Res Commun 1975; 66: 1281-6.
65. Wlodarska I, Veyt E, De Paepe P, et al. FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations. Leukemia 2005; 19: 1299-305.
66. Fox SB, Brown P, Han C, et al. Expression of the forkhead transcription factor FOXP1 is associated with estrogen receptor alpha and improved survival in primary human breast carcinomas. Clin Cancer Res 2004; 10: 3521-7.
67. Giatromanolaki A, Koukourakis MI, Sivridis E, Gatter KC, Harris AL, Banham AH. Loss of expression and nuclear/cytoplasmic localization of the FOXP1 forkhead transcription factor are common events in early endometrial cancer: relationship with estrogen receptors and HIF-1alpha expression. Mod Pathol 2006; 19: 9-16.
68. Huebner K. Tumor suppressors on 3p: a neoclassic quartet. Proc Natl Acad Sci U S A 2001; 98: 14763-5.
69. Zabarovsky ER, Lerman MI, Minna JD. Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers. Oncogene 2002; 21: 6915-35.
70. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429: 457-63.
71. Scott GK, Mattie MD, Berger CE, Benz SC, Benz CC. Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res 2006; 66: 1277-81.
72. Saito Y, Liang G, Egger G, et al. Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 2006; 9: 435-43.
dc.identifier.urihttp://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22431-
dc.description.abstract口腔癌的普及率在全球常見癌症中排名第八,且發生在男性的機率特別高。結締組織生長因子CTGF是CCN (Cyr61,CTGF,NOV) 家族中一種分泌型的基質細胞蛋白,能引發許多基本生物及病理的發展。近年來,我們發現CTGF的表現與腫瘤發展與增生有一定的關係。但是,最近的研究指出CTGF在不同癌症中有相反的功能,而它在口腔癌所扮演的角色至今仍不清楚。在此我們本實驗研究CTGF在口腔癌侵入及轉移中扮演的生物學的作用與下游調控機制。內生性的CTGF表現量與有較高侵襲能力及轉移淺力的口腔癌細胞株呈現負相關。使CTGF過度表現或利用重組CTGF蛋白的做法可減少惡性度高的人類SAS細胞株侵入與移動的能力。建構small hairpin RNA (shRNA)轉染到人類TW2.6細胞株內,抑制CTGF的表現後,發現癌細胞的侵入及轉移能力有明顯增強。為了更進一步了解CTGF調控口腔癌發展的機制,我們進行microRNA的微陣列分析,結果發現,有CTGF表現的細胞株與控制組相比後,miR-504的表現量下降。且在穩定大量表現CTGF的細胞株內,使miR-504大量表現後,發現回復細胞侵入與轉移的能力。使用生物資訊分析預測miR-504下游的標靶基因,找出FOXP1為其中之一。首先利用半定量PCR方式分析FOXP1的mRNA表現量,發現跟控制組比較之後在大量表現CTGF的細胞株內上升,而在CTGF被抑制的細胞株內則表現量下降。我們進一步利用small hairpin RNA (shRNA)轉染CTGF表現及控制組細胞株,抑制FOXP1的表現後,則細胞侵入及移動的能力則大幅增加。由這些發現我們可以了解,利用CTGF抑制口腔癌細胞是有前瞻性的。本實驗證明CTGF可藉由調控miR-504及其下游的FOXP1這條訊息傳遞路徑來達到顯著抑制人類口腔鱗狀細胞侵入及轉移能力的效果,且指出CTGF可能是為口腔癌發展中的癌症抑制基因。zh_TW
dc.description.abstractThe prevalence of oral cancer is the eighth most common cancer worldwide and is particularly high among men. Connective tissue growth factor (CTGF), a secreted matricellular protein of CCN family engages a wide variety of basic biological and pathological processes. Recently, CTGF expression has been shown to be associated with tumor development and progression. However, recent studies demonstrated that CTGF seems to have opposite functions in different cancers and its role in oral cancer is still unknown. Here we investigated that the biological roles and underlying regulation mechanism of CTGF in oral cancer invasion and metastasis. Endogenous CTGF expression negatively correlates with invasive and metastatic potential of oral cancer cell lines. CTGF overexpression or recombinant CTGF protein treatment decreased the invasion and migration abilities in SAS cells. Transfected-small hairpin RNA (shRNA) constructs to target human CTGF in TW2.6 cells resulted in enhancement of cell invasion and migration. To further investigate the mechanism of CTGF regulated oral cancer progression, we performed microRNA microarray. The results showed that miR-504 was downregulation in CTGF transfectants compared to NEO control. Overexpression of miR-504 restored the invasion and migration abilitities of CTGF overexpression stable clones. Using bioinformatic prediction, FOXP1 was recognized as one of several miR-504 target genes. We analyzed the mRNA levels of FOXP1 by RT-PCR and found that mRNA level was increased in SAS/CTGF stable clones and decreased in TW2.6/shCTGF stable clones versus control. We further transfected-small hairpin RNA (shRNA) constructs to target human FOXP1 in CTGF-transfectants and control cells resulted in enhancement of cell invasion and migration. These findings illustrated that CTGF inhibited tumor progression in oral cancer cells. Our study demonstrated that CTGF regulated miR-504 through FOXP1 signaling significantly inhibited migration and invasion abilities in human oral squamous cells, suggesting that CTGF may be a tumor suppressor gene during oral cancer progression.en
dc.description.provenanceMade available in DSpace on 2021-06-08T04:17:39Z (GMT). No. of bitstreams: 1
ntu-99-R97450010-1.pdf: 2645143 bytes, checksum: 312ccfc6892224931cb96d68068957fd (MD5)
Previous issue date: 2010
en
dc.description.tableofcontentsCONTENTS
INTRODUCTION……………………………………………....1
MATERIALS AND METHODS…………………………….....5
RESULTS…………………………………………………...….11
1. CTGF expression is negatively correlated with metastatic potential of human oral cancer cell lines.
2. Overexpression of CTGF inhibits invasion and migration abilities in human oral cancer cells.
3. Knockdown of CTGF enhances human oral cancer cells invasion and migration abilities.
4. CTGF regulate metastasis in oral cancer cells through microRNAs.
5. Overexpression of miR-346 has no effect on invasion and migration abilities in CTGF-transfectants.
6. Overexpression of miR-346 has no effect on invasion and migration abilities in CTGF-transfectants.
7. Overexpression of miR-504 restored invasion and migration abilities in CTGF-transfectants.
8. FOXP1 is the downstream target gene of CTGF regulated miR-504 signaling pathway.
DISCUSSION……………………………………………….....17
FIGURES……………………………………………………....21
TABLES…………………………………………………..……40
REFERENCES………………………………………...………43
dc.language.isoen
dc.title結締組織生長因子在口腔鱗狀上皮細胞癌所扮演的角色探討zh_TW
dc.titleThe Role of Connective Tissue Growth Factor in Human Oral Squamous Cell Carcinomaen
dc.typeThesis
dc.date.schoolyear98-2
dc.description.degree碩士
dc.contributor.coadvisor郭彥彬(Mark Yen-Ping Kuo)
dc.contributor.oralexamcommittee楊慕華(Muh-Hwa Yang)
dc.subject.keyword結締組織生長因子,微核醣核酸,癌症發展,移動,侵入,zh_TW
dc.subject.keywordCTGF,microRNA,cancer progression,migration,invasion,en
dc.relation.page48
dc.rights.note未授權
dc.date.accepted2010-07-29
dc.contributor.author-college牙醫專業學院zh_TW
dc.contributor.author-dept口腔生物科學研究所zh_TW
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