Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20101
標題: XPC的表現在非小細胞肺癌中之意義
The Role of Xeroderma Pigmentosum group C (XPC) Expression in Non-Small Cell Lung Cancer
作者: 卓信慶
Cho, Hsin-Ching
關鍵字: nucleotide excision repair;核苷酸切除修復;Xeroderma pigmentosum group C;non-small cell lung cancer;著色性乾皮症;非小細胞肺癌
出版社: 生物醫學研究所
引用: 參考文獻 行政院衛生署台灣地區主要死因歷年統計結果 (2004) 中華民國行政院衛生署。 Adimoolam S, Ford JM. (2002) p53 and DNA damage-inducible expression of the xeroderma pigmentosum group C gene. Proc Natl Acad Sci U S A. 99, 12985-90. Adimoolam S, Ford JM. (2003) p53 and regulation of DNA damage recognition during nucleotide excision repair. DNA Repair. 2, 947-54. Araki M, Masutani C, Takemura M, Uchida A, Sugasawa K, Kondoh J, Ohkuma Y, Hanaoka F. (2001) Centrosome protein centrin 2/caltractin 1 is part of the xeroderma pigmentosum group C complex that initiates global genome nucleotide excision repair. J Biol Chem. 276, 18665-72. Araujo SJ, Wood RD. (1999) Protein complexes in nucleotide excision repair. Mutat Res. 435, 23-33. Bar J, Cohen-Noyman E, Geiger B, Oren M. (2004) Attenuation of the p53 response to DNA damage by high cell density. Oncogene. 23, 2128-37 Bartek J, Lukas C, Lukas J. (2004) Checking on DNA damage in S phase. Nat Rev Mol Cell Biol. 5, 792-804. Batty DP, Wood RD. (2000) Damage recognition in nucleotide excision repair of DNA. Gene. 241, 193-204. Chang LC, Sheu HM, Huang YS, Tsai TR, Kuo KW. (1999) A novel function of emodin: enhancement of the nucleotide excision repair of UV- and cisplatin-induced DNA damage in human cells. Biochem Pharmacol. 58, 49-57. Cleaver JE. (2001) Xeroderma pigmentosum: the first of the cellular caretakers. Trends Biochem Sci. 26, 398-401. Cleaver JE. (2004) Excision repair--the first steps into mammalian cells. DNA Repair. 3, 91-99. Cline SD, Hanawalt PC. (2003) Who''s on first in the cellular response to DNA damage? Nat Rev Mol Cell Biol. 4, 361-72. De laat WL, Jaspers NG, Hoeijmakers JH. (1999) Molecular mechanism of nucleotide excision repair. Genes Dev. 13, 768-85. Demonacos C, Krstic-Demonacos M, Smith L, Xu D, O''Connor DP, Jansson M, La Thangue NB. (2004) A new effector pathway links ATM kinase with the DNA damage response. Nat Cell Biol. 6, 968-76. Dohoney KM, Guillerm C, Whiteford C, Elbi C, Lambert PF, Hager GL, Brady JN. (2004) Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage. Oncogene. 23,49-57. Fautrel A, Andrieux L, Musso O, Boudjema K, Guillouzo A, Langouet S. (2005) Overexpression of the two nucleotide excision repair genes ERCC1 and XPC in human hepatocellular carcinoma. J Hepatol. 43, 288-93. Fei P, El-Deiry WS. (2003) P53 and radiation responses. Oncogene. 22, 5774-83. Ferguson BE, Oh DH. (2005) Proficient global nucleotide excision repair in human keratinocytes but not in fibroblasts deficient in p53. Cancer Res. 65, 8723-9. Fitch ME, Cross IV, Ford JM. (2003) p53 responsive nucleotide excision repair gene products p48 and XPC, but not p53, localize to sites of UV-irradiation-induced DNA damage, in vivo. Carcinogenesis. 24, 843-50. Ford JM, Hanawalt PC. (1995) Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance. Proc Natl Acad Sci U S A. 92, 8876-80. Ford JM, Hanawalt PC. (1997) Expression of wild-type p53 is required for efficient global genomic nucleotide excision repair in UV-irradiated human fibroblasts. J Biol Chem. 272, 28073-80. Friedberg EC. (2003) DNA damage and repair. Nature. 421, 436-40. Friedberg EC, Bond JP, Burns DK, Cheo DL, Greenblatt MS, Meira LB, Nahari D, Reis AM. (2000) Defective nucleotide excision repair in xpc mutant mice and its association with cancer predisposition. Mutat Res. 459, 99-108. Friedberg EC. (2004) The discovery that xeroderma pigmentosum (XP) results from defective nucleotide excision repair. DNA Repair. 3, 183-195. Hey T, Lipps G, Sugasawa K, Iwai S, Hanaoka F, Krauss G. (2002) The XPC-HR23B complex displays high affinity and specificity for damaged DNA in a true-equilibrium fluorescence assay. Biochemistry. 41, 6583-7. Hoeijmakers JH. (2001) Genome maintenance mechanisms for preventing cancer. Nature. 411, 366-74. Hollander MC, Philburn RT, Patterson AD, Velasco-Miguel S, Friedberg EC, Linnoila RI, Fornace AJ Jr. (2005) Deletion of XPC leads to lung tumors in mice and is associated with early events in human lung carcinogenesis. Proc Natl Acad Sci U S A. 102, 13200-5. Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T, Hovig E, Smith-Sorensen B, Montesano R, Harris CC. (1994) Database of p53 gene somatic mutations in human tumors and cell lines. Nucleic Acids Res. 22, 3551-5. Hoogervorst EM, van Steeg H, de Vries A. (2005) Nucleotide excision repair- and p53-deficient mouse models in cancer research. Mutat Res. 574, 3-21. Jackson SP. (2002) Sensing and repairing DNA double-strand breaks. Carcinogenesis. 23, 687-96. Janicijevic A, Sugasawa K, Shimizu Y, Hanaoka F, Wijgers N, Djurica M, Hoeijmakers JH, Wyman C. (2003) DNA bending by the human damage recognition complex XPC-HR23B. DNA Repair. 2, 325-36. Kartalou M, Essigmann JM. (2001) Mechanisms of resistance to cisplatin. Mutat Res. 478, 23-43. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW. (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51, 6304-11. Khan SG, Muniz-Medina V, Shahlavi T, Baker CC, Inui H, Ueda T, Emmert S, Schneider TD, Kraemer KH. (2002) The human XPC DNA repair gene: arrangement, splice site information content and influence of a single nucleotide polymorphism in a splice acceptor site on alternative splicing and function. Nucleic Acids Res. 30, 3624-31. Khanna KK, Jackson SP. (2001) DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 27, 247-54. Lehmann AR. (2003) DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Biochimie. 85, 1101-11. Levine AJ. (1997) p53, the cellular gatekeeper for growth and division. Cell. 88, 323-31. Li L, Lu X, Peterson C, Legerski R. (1997) XPC interacts with both HHR23B and HHR23A in vivo. Mutat Res. 383, 197-203. Liedert B, Pluim D, Schellens J, Thomale J. (2006) Adduct-specific monoclonal antibodies for the measurement of cisplatin-induced DNA lesions in individual cell nuclei. Nucleic Acids Res. 34, 1-12. Liu L, Parekh-Olmedo H, Kmiec EB. (2003) The development and regulation of gene repair. Nat Rev Genet. 4, 679-89. Loehrer PJ, Einhorn LH. (1984) Drugs five years later. Cisplatin. Ann Intern Med. 100, 704-13. Masutani C, Araki M, Sugasawa K, van der Spek PJ, Yamada A, Uchida A, Maekawa T, Bootsma D, Hoeijmakers JH, Hanaoka F. (1997) Identification and characterization of XPC-binding domain of hHR23B. Mol Cell Biol. 17, 6915-23. Masutani C, Sugasawa K, Yanagisawa J, Sonoyama T, Ui M, Enomoto T, Takio K, Tanaka K, van der Spek PJ, Bootsma D, et al. (1994) Purification and cloning of a nucleotide excision repair complex involving the xeroderma pigmentosum group C protein and a human homologue of yeast RAD23. EMBO J. 13, 1831-43. McKay BC, Becerril C, Ljungman M. (2001) P53 plays a protective role against UV- and cisplatin-induced apoptosis in transcription-coupled repair proficient fibroblasts. Oncogene. 20, 6805-8. Meira LB, Reis AM, Cheo DL, Nahari D, Burns DK, Friedberg EC. (2001) Cancer predisposition in mutant mice defective in multiple genetic pathways: uncovering important genetic interactions. Mutat Res. 477, 51-8. Mol CD, Parikh SS, Putnam CD, Lo TP, Tainer JA. (1999) DNA repair mechanisms for the recognition and removal of damaged DNA bases. Annu Rev Biophys Biomol Struct. 28, 101-28. Nahari D, McDaniel LD, Task LB, Daniel RL, Velasco-Miguel S, Friedberg EC. (2004) Mutations in the Trp53 gene of UV-irradiated Xpc mutant mice suggest a novel Xpc-dependent DNA repair process. DNA Repair. 3, 379-86. Nelson WG, Kastan MB. (1994) DNA strand breaks: the DNA template alterations that trigger p53-dependent DNA damage response pathways. Mol Cell Biol. 14, 1815-23. Ng JM, Vermeulen W, van der Horst GT, Bergink S, Sugasawa K, Vrieling H, Hoeijmakers JH. (2003) A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein. Genes Dev. 17, 1630-45. Norbury CJ, Zhivotovsky B. (2004) DNA damage-induced apoptosis. Oncogene. 23, 2797-808. Okuda Y, Nishi R, Ng JM, Vermeulen W, van der Horst GT, Mori T, Hoeijmakers JH, Hanaoka F, Sugasawa K. (2004) Relative levels of the two mammalian Rad23 homologs determine composition and stability of the xeroderma pigmentosum group C protein complex. DNA Repair. 3, 1285-95. Pegg AE. (1999) DNA repair pathways and cancer prevention. Adv Exp Med Biol. 472, 253-67. Poirier MC. (2004) Chemical-induced DNA damage and human cancer risk. Nat Rev Cancer. 4, 630-7. Pollack JR, Iyer VR. (2002) Characterizing the physical genome. Nat Genet. 32, 515-21. Rehemtulla A, Hamilton CA, Chinnaiyan AM, Dixit VM. (1997) Ultraviolet radiation-induced apoptosis is mediated by activation of CD-95 (Fas/APO-1). J Biol Chem. 272, 25783-6. Sengupta S, Harris CC. (2005) p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol. 6, 44-55. Shimizu Y, Iwai S, Hanaoka F, Sugasawa K. (2003) Xeroderma pigmentosum group C protein interacts physically and functionally with thymine DNA glycosylase. EMBO J. 22, 164-73. Sugasawa K, Masutani C, Hanaoka F. (1993) Cell-free repair of UV-damaged simian virus 40 chromosomes in human cell extracts. I. Development of a cell-free system detecting excision repair of UV-irradiated SV40 chromosomes. J Biol Chem. 268, 9098-104. Sugasawa K, Masutani C, Uchida A, Maekawa T, van der Spek PJ, Bootsma D, Hoeijmakers JH, Hanaoka F. (1996) HHR23B, a human Rad23 homolog, stimulates XPC protein in nucleotide excision repair in vitro. Mol Cell Biol. 16, 4852-61. Sugasawa K, Ng JM, Masutani C, Iwai S, van der Spek PJ, Eker AP, Hanaoka F, Bootsma D, Hoeijmakers JH. (1998) Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Mol Cell. 2, 223-32. Sugasawa K, Ng JM, Masutani C, Maekawa T, Uchida A, van der Spek PJ, Eker AP, Rademakers S, Visser C, Aboussekhra A, Wood RD, Hanaoka F, Bootsma D, Hoeijmakers JH. (1997) Two human homologs of Rad23 are functionally interchangeable in complex formation and stimulation of XPC repair activity. Mol Cell Biol. 17, 6924-31. Sugasawa K, Okamoto T, Shimizu Y, Masutani C, Iwai S, Hanaoka F. (2001) A multistep damage recognition mechanism for global genomic nucleotide excision repair. Genes Dev. 15, 507-21. Tornaletti S, Rozek D, Pfeifer GP. (1994) Mapping of UV photoproducts along the human P53 gene. Ann N Y Acad Sci. 726, 324-6. Uchida A, Sugasawa K, Masutani C, Dohmae N, Araki M, Yokoi M, Ohkuma Y, Hanaoka F. (2002) The carboxy-terminal domain of the XPC protein plays a crucial role in nucleotide excision repair through interactions with transcription factor IIH. DNA Repair. 1, 449-61. Van der Spek PJ, Eker A, Rademakers S, Visser C, Sugasawa K, Masutani C, Hanaoka F, Bootsma D, Hoeijmakers JH. (1996) XPC and human homologs of RAD23: intracellular localization and relationship to other nucleotide excision repair complexes. Nucleic Acids Res. 24, 2551-9. Van der Spek PJ, Smit EM, Beverloo HB, Sugasawa K, Masutani C, Hanaoka F, Hoeijmakers JH, Hagemeijer A. (1994) Chromosomal localization of three repair genes: the xeroderma pigmentosum group C gene and two human homologs of yeast RAD23. Genomics. 23, 651-8. Venema J, van Hoffen A, Karcagi V, Natarajan AT, van Zeeland AA, Mullenders LH. (1991) Xeroderma pigmentosum complementation group C cells remove pyrimidine dimers selectively from the transcribed strand of active genes. Mol Cell Biol. 11, 4128-34. Vousden KH, Lu X. (2002) Live or let die: the cell''s response to p53. Nat Rev Cancer. 2, 594-604. Wang G, Dombkowski A, Chuang L, Xu XX. (2004) The involvement of XPC protein in the cisplatin DNA damaging treatment-mediated cellular response. Cell Res. 14, 303-14. Wang QE, Zhu Q, Wani G, Chen J, Wani AA. (2004) UV radiation-induced XPC translocation within chromatin is mediated by damaged-DNA binding protein, DDB2. Carcinogenesis. 25, 1033-43. Wang QE, Zhu Q, Wani G, El-Mahdy MA, Li J, Wani AA. (2005) DNA repair factor XPC is modified by SUMO-1 and ubiquitin following UV irradiation. Nucleic Acids Res. 33, 4023-34. Wang QE, Zhu Q, Wani MA, Wani G, Chen J, Wani AA. (2003) Tumor suppressor p53 dependent recruitment of nucleotide excision repair factors XPC and TFIIH to DNA damage. DNA Repair. 2, 483-99. Wani MA, Zhu QZ, El-Mahdy M, Wani AA. (1999) Influence of p53 tumor suppressor protein on bias of DNA repair and apoptotic response in human cells. Carcinogenesis. 20, 765-72. Wood RD, Mitchell M, Sgouros J, Lindahl T. (2001) Human DNA repair genes. Science. 291, 1284-9. Yokoi M, Masutani C, Maekawa T, Sugasawa K, Ohkuma Y, Hanaoka F. (2000) The xeroderma pigmentosum group C protein complex XPC-HR23B plays an important role in the recruitment of transcription factor IIH to damaged DNA. J Biol Chem. 275, 9870-5. You JS, Wang M, Lee SH. (2003) Biochemical analysis of the damage recognition process in nucleotide excision repair. J Biol Chem. 278, 7476-85. Yu Z, Chen J, Ford BN, Brackley ME, Glickman BW. (1999) Human DNA repair systems: an overview. Environ Mol Mutagen. 33, 3-20. Zurer I, Hofseth LJ, Cohen Y, Xu-Welliver M, Hussain SP, Harris CC, Rotter V. (2004) The role of p53 in base excision repair following genotoxic stress. Carcinogenesis. 25, 11-9.
摘要: 
DNA帶有生物體重要之遺傳訊息,調控著細胞的生理機制以維持正常運作。DNA修復機制必須被活化才能修復DNA傷害,進而避免細胞死亡、減少突變以及維持基因體(Genome)之完整性。XPC是一重要的DNA損傷辨識蛋白,特別是在核苷酸切補修復作用中扮演重要角色。在本研究中,首先我們想要探討在非小細胞肺癌中XPC的表現,進一步了解紫外線與cisplain所誘發的XPC與非小細胞肺癌的相關性。
首先利用RT-PCR的方法,偵測非小細胞肺癌中XPC的表現。結果顯示,約有43%的非小細胞肺癌細胞株以及臨床肺癌組織檢體表現XPC mRNA。此外,我們自行製備XPC單株抗體,利用西方墨點法偵測XPC的表現。結果顯示在H226、H838與A549細胞中,XPC的表現明顯大於H23、H1437、H2009與H2087細胞。除此之外,以免疫組織染色法的方式,我們觀察20%的非小細胞肺癌病人組織表現XPC。在紫外線照射或抗癌藥物cisplatin處理下,會增加A549細胞中XPC的表現,但是在H226細胞中表現量卻是下降,然而,不論是在A549或H226細胞,都會誘發p53的表現。
根據以上實驗結果顯示,肺癌細胞可以表現XPC,特別是在DNA損傷後會誘發XPC的表現。然而,隨著紫外線照射下,我們發現A549細胞的存活率大於其它肺癌細胞。綜合本研究結果我們認為在非小細胞肺癌中,XPC表現的程度可能與治療的抗藥性有關。

DNA contains genetic information for processing and regulating cell's normal physiological functions. Therefore, maintaining intact DNA structure is essential for cells' stress response, in particular, the cell stress that is associated with DNA damage, which could be remedied by DNA repair mechanism to preserve the integrity of genome, to reduce mutation frequencies, and to avoid cell death. Xeroderma pigmentosum group C (XPC) protein is an important DNA damage recognition protein for nucleotide excision repair (NER). In this thesis, we studied the role of XPC expression in non-small cell lung cancer (NSCLC) and analyzed its activation upon UV irradiation or cisplatin treatment in NSCLC cells.
Our results showed that expression of XPC mRNA was identified in three of seven lung adenocarcinoma cell lines, and in about forty-three percent of human NSCLC tissues by RT-PCR. Furthermore, by using self-prepared monoclonal antibodies to XPC, we found that XPC content in A549, H226 and H838 cells was higher than that in H23, H1437, H2009 and H2087 cells. Clinically, XPC protein was detected in about twenty percent of NSCLC tissues by immunohistochemistry. In vitro, after UV irradiation or cisplatin treatment, XPC expression was increased in A549 cells, but it was decreased in H226 cells. However, p53 expression was increased in both A549 and H226 cells in response to DNA damage.
These results indicated that lung adenocarcinoma cells expressed XPC protein, and DNA damaging agent could increase XPC expression. Moreover, survival rate of A549 cells following UV irradiation was highest among all cell lines. These data suggest that level of XPC expression in NSCLC may be correlated with resistance to the therapy.
URI: http://hdl.handle.net/11455/20101
其他識別: U0005-1708200611263400
Appears in Collections:生物醫學研究所

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