中文摘要
肺癌為國人癌症死亡的首位，近年來每年約有6000人死於肺癌，但其分子致癌機制至今仍未釐清。由於癌症的形成過程中主要變異的基因為致癌基因 (Oncogenes) 活性過增或抑癌基因 (Tumor suppress genes, TSGs) 失去活性；抑癌基因經研究證明需二個基因座皆變異才導致其失去活性而致癌，其變異的方式多為一基因座產生點突變、小片段鹼基缺失、或啟動子過度甲基化 (promoter hypermethylation)，而另一基因座產生抑癌基因及鄰近區域DNA大片段的缺失，因此異質性缺失 (loss of heterozygosity, LOH) 經常可作為抑癌基因區位的指標。為了偵測肺癌組織之異質性缺失，並瞭解一些特定抑癌基因參與台灣肺癌形成之機制，本研究設計了以下三個主要目標：（1）以微切片（microdissection）取得高純度癌細胞與其配對之正常細胞進行基因體異質性缺失分析，以建立一台灣肺癌基因體異質性缺失圖譜；（2）針對缺失的高頻率區域如染色體1p36.2、10q24.3及 17q24.3所包含的三個抑癌基因ICAT、BTRCP及 AXIN2在肺癌病人中進行DNA、RNA、蛋白質變異分析；（3）針對基因體缺失區域17q24.3設計高密度之微衛星序列，以精確定出缺失區位，再進一步以肺癌細胞株及病人組織進行該區位之異常轉錄產物及啟動子甲基化分析。
目標一：本研究結果顯示以177個微衛星序列進行71位肺癌病人的基因體缺失分析，有20個染色體區位其缺失頻率可達48％以上，其中8個區位尚未有文獻報告，僅在台灣發現；卡方分析統計的結果顯示許多區位的缺失與病人的年齡、性別、抽煙狀況、癌症種類及分期有關，例如：9個微衛星序列與抽煙的病人有關（P值小於0.05）；2個微衛星序列與肺腺癌 (adenocarcinoma) 有關（P值小於0.05）。利用Cox’s多變項分析，3個區位的缺失與病人存活率顯著相關（P值小於0.05）。上述為文獻中針對肺癌最完整的全基因異質性缺失研究，這些與台灣地區非小細胞肺癌有關的異質性缺失，可能用來作為肺癌早期偵測的指標或預後的依據，同時這些區域也可用來尋找一些因為失去功能而導致非小細胞肺癌形成的新穎抑癌基因。
目標二：上述基因體異質性缺失結果顯示，染色體1p36.2、10q24.3及 17q24.3 其基因體缺失的頻率皆高於40%，這三個基因座分別包含wingless (Wnt) 訊號傳遞中的三個重要抑癌基因ICAT、BTRCP及 AXIN2；而Wnt 訊號傳遞與細胞增生、活動及癌化生成是有關連的，並與β-catenin蛋白質降解過程中扮演重要角色。為瞭解在非小細胞肺癌中，AXIN2、BTRCP及ICAT基因是否發生變異，我們利用反轉錄-聚合及免疫組織化學染色法偵測78位非小細胞肺癌及非腫瘤配對肺組織中AXIN2、BTRCP及ICAT基因之異常。研究結果顯示，分別有35%、32%及35%的病人有蛋白質表現異常之情形，其啟動子過度甲基化 (promoter hypermethylation) 亦分別有38%、50%及42%。卡方分析發現AXIN2 mRNA低表現經常發生於腫瘤分期之早期病人，其比例為53%（P值為0.028）；另外免疫組織化學染色法與卡方分析結果顯示AXIN2、BTRCP及ICAT基因蛋白低表現與啟動子過度甲基化顯著相關 (P值<0.001) 而且與β-catenin蛋白過度累積於細胞核中有顯著相關性（AXIN2，P值為0.004；BTRCP，P值為0.013）。顯示抑癌基因ICAT、BTRCP及 AXIN2變異與非小細胞肺癌形成及β-catenin蛋白過度累積有關。本研究結果亦為第一篇針對Wnt pathway之相關抑癌基因AXIN2、BTRCP及ICAT在癌症組織樣本中的完整分子及臨床研究。
目標三：基因體異質性缺失的研究顯示，染色體17q24.3 其缺失的頻率高於50%，推測此區可能有新腫瘤抑制基因。因此我們利用精確缺失定位分析17q24.3在肺癌中之情形，並且針對位於此區之新穎基因LOC51321檢測其在15株肺癌細胞株及53個肺癌組織中各有47%及36%其mRNA低表達的情形。另外，肺癌細胞株CL1-5-F4之LOC51321啟動子甲基化情形及mRNA不表達有相關性。因此推測此新穎基因LOC51321可能參與肺癌形成，且其變異與異質性缺失及啟動子過度甲基化相關。

ABSTRACT
Lung cancer is the leading cause of cancer deaths in Taiwan. It has been shown that alterations of tumor suppressor genes (TSGs) involve in the multi-step carcinogenesis of human cancer including lung cancer. Both copies of TSGs have to be inactivated for their function to be lost. Therefore, to search for the genomic regions that potentially contain the TSGs and to investigate the etiological association of allelic deletion in candidate TSGs in lung cancer, this study is designed to conduct (1) genome-wide loss of heterozygosity (LOH) analysis in microdissected surgically resected lung tumors to prescreen the potential chromosomal regions containing TSGs; (2) gene/protein alteration studies on high LOH regions at 1p36.2, 10q24.3, and 17q24.3 including genes encoding the ICAT, BTRCP and AXIN2 proteins respectively that involved in the β-catenin/wingless (Wnt) regulation pathway, in tumors from 78 cancer patients; and (3) high density LOH analysis at 17q24.3 chromosomal region and refined mapping of candidate TSG, LOC51321, by analyzing aberrant transcripts and promoter hypermethylation of in lung tumor tissues and cancer cell lines.
Aim 1: The genome-wide LOH analysis using 177 microsatellite markers in 71 microdissected surgical lung tumors and paired normal cells indicated that 20 markers showed an LOH frequency greater than 48%, and eight of them (2p23.3, 2p24.3, 2q35, 6p22.2, 7p14.3, 7p22.2, 17q24.3 and 21q22.3) were novel in non-small cell lung cancer (NSCLC). In addition, markers specifically associated with clinicopathological parameters such as ages, sexes, smoking habits, tumor types, and tumor stages were identified. For example, there were nine markers specifically associated with patients who smoked (P<0.05). The markers D14S1426 and D20S186 were also associated with adenocarcinoma (AD) patients (P<0.05). Furthermore, three markers, D2S2968, D6S2439, and D7S1818, were significantly associated with poor prognosis of NSCLC patients using both univariate and multivariate Cox’s regression analyses (P<0.05). These markers can be potentially used for early lung cancer detection, outcome measurement, and positional cloning of new TSGs.

Aim 2: Chromosome regions at 1p36.2, 10q24.3, and 17q24.3 showed a high frequency of LOH in tumors from NSCLC patients. These frequently deleted regions included gene loci encoding the ICAT (inhibitor of β-catenin and TCF-4), BTRCP (β transducin repeat containing protein), and AXIN2 (Axis inhibition protein 2) proteins, which were putative tumor suppressor proteins involved in regulating the Wnt signaling pathway. Therefore, we further investigated the possibility of alterations of ICAT, BTRCP, and AXIN2 including loss of protein/mRNA expression and promoter hypermethylation and allelic imbalance in 78 NSCLC patients. The gene/protein alterations with clinical associations were also examined. The β-catenin deregulation was significantly attributable to low mRNA/protein expression of AXIN2 (P = 0.004) and BTRCP (P = 0.013). A high concordance was observed between low protein/mRNA expression and promoter hypermethylation (P < 0.001) for the AXIN2, BTRCP, and ICAT genes. Our data provide compelling evidence for an inverse correlation of AXIN2, BTRCP, and ICAT expression with β-catenin expression in the NSCLC tumorigenesis and suggest that promoter hypermethylation is the predominant mechanism in AXIN2, BTRCP, and ICAT alterations.
Aim 3: Based on our genome-wide LOH data, chromosome region at 17q24.3 was a novel frequent LOH region in NSCLC. The refined mapping using 9 additional markers was then performed on chromosome 17q24.3. The allelic loss pattern of 48 tumors suggests that the minimal deletion region was located between markers D17S1882 and D17S2193, spanning a distance of approximately 2.7 Mb and reaching 65% LOH at locus D17S1816. A putative gene LOC51321 was speculated to be a deletion target on 17q24.3 in NSCLC. The expression analysis indicated decreased expression of LOC51321 in 47% (7/15) of the NSCLC cell lines and 36% (19/53) of the tumor tissues. In addition, 5-Aza-deoxycytosine successfully restored mRNA expression and de-methylated the putative promoter region in CL1-5-F4 cells that lacked LOC51321 expression and that harbored a methylated respective promoter. The results showed that LOC51321 may be involved in lung tumorigenesis.

REFERENCES

1. Department of Health, The executive Yuan, Republic of China. General Health Statistics, 1998. pp. 86-108.
2. Chen, C. J., Wu, H. Y., Chuang, Y. C., Chang, A. S., Luh, K. T., Chao, H. H., Chen, K. Y., Chen, S. G., Lai, G. M., and Huang, H. H. Epidemiologic characteristics and multiple risk factors of lung cancer in Taiwan. Anticancer Res, 10: 971-976, 1990.
3. http://www.doh.gov.tw/statistic/index.htm.
4. Minna, J. D., Sekido, Y., Fong, K., and Gazdar, A. F. Cancer, 5 edition, p. 849-857: Lippincott: Philadelphia, 1997.
5. Bains, M. S. Surgical treatment of lung cancer. Chest, 100: 826-837, 1991.
6. Mountain, C. F. The international system for staging lung cancer. Semin Surg Oncol, 18: 106-115, 2000.
7. Fearon, E. R. Human cancer syndromes: clues to the origin and nature of cancer. Science, 278: 1043-1050, 1997.
8. Knudson, A. G. Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol, 122: 135-140, 1996.
9. Kohno, T. and Yokota, J. How many tumor suppressor genes are involved in human lung carcinogenesis? Carcinogenesis, 20: 1403-1410, 1999.
10. Borczuk, A. C., Gorenstein, L., Walter, K. L., Assaad, A. A., Wang, L., and Powell, C. A. Non-small-cell lung cancer molecular signatures recapitulate lung developmental pathways. Am J Pathol, 163: 1949-1960., 2003.
11. Meuwissen, R. and Berns, A. Mouse models for human lung cancer. Genes Dev, 19: 643-664., 2005.
12. Giovino, G. A. Epidemiology of tobacco use in the United States. Oncogene, 21: 7326-7340., 2002.
13. Massion, P. P. and Carbone, D. P. The molecular basis of lung cancer: molecular abnormalities and therapeutic implications. Respir Res, 4: 12. Epub 2003 Oct 2007., 2003.
14. Wistuba, II, Mao, L., and Gazdar, A. F. Smoking molecular damage in bronchial epithelium. Oncogene, 21: 7298-7306., 2002.
15. Minna, J. D., Fong, K., Zochbauer-Muller, S., and Gazdar, A. F. Molecular pathogenesis of lung cancer and potential translational applications. Cancer J, 8: S41-46., 2002.
16. Travis, W. D. Pathology of lung cancer. Clin Chest Med, 23: 65-81, viii., 2002.
17. Wistuba, II and Gazdar, A. F. Characteristic genetic alterations in lung cancer. Methods Mol Med, 74: 3-28., 2003.
18. Osada, H. and Takahashi, T. Genetic alterations of multiple tumor suppressors and oncogenes in the carcinogenesis and progression of lung cancer. Oncogene, 21: 7421-7434., 2002.
19. Sozzi, G. Molecular biology of lung cancer. Eur J Cancer, 37, 2001.
20. Bassing, C. H. and Alt, F. W. The cellular response to general and programmed DNA double strand breaks. DNA Repair (Amst), 3: 781-796., 2004.
21. Jackson, S. P. Sensing and repairing DNA double-strand breaks. Carcinogenesis, 23: 687-696., 2002.
22. Goodhead, D. T. Initial events in the cellular effects of ionizing radiations: clustered damage in DNA. Int J Radiat Biol, 65: 7-17., 1994.
23. Ward, J. F. Radiation mutagenesis: the initial DNA lesions responsible. Radiat Res, 142: 362-368., 1995.
24. Karagiannis, T. C. and El-Osta, A. Epigenetic changes activate widespread signals in response to double-strand breaks. Cancer Biol Ther, 3: 617-623, 2004.
25. Ferguson, D. O. and Alt, F. W. DNA double strand break repair and chromosomal translocation: lessons from animal models. Oncogene, 20: 5572-5579., 2001.
26. Shiloh, Y. ATM and ATR: networking cellular responses to DNA damage. Curr Opin Genet Dev, 11: 71-77., 2001.
27. Testa, J. R., Liu, Z., Feder, M., Bell, D. W., Balsara, B., Cheng, J. Q., and Taguchi, T. Advances in the analysis of chromosome alterations in human lung carcinomas. Cancer Genet Cytogenet, 95: 20-32., 1997.
28. Draviam, V. M., Xie, S., and Sorger, P. K. Chromosome segregation and genomic stability. Curr Opin Genet Dev, 14: 120-125., 2004.
29. Charames, G. S. and Bapat, B. Genomic instability and cancer. Curr Mol Med, 3: 589-596., 2003.
30. Ionov, Y., Peinado, M. A., Malkhosyan, S., Shibata, D., and Perucho, M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature, 363: 558-561., 1993.
31. Lawes, D. A., SenGupta, S., and Boulos, P. B. The clinical importance and prognostic implications of microsatellite instability in sporadic cancer. Eur J Surg Oncol, 29: 201-212., 2003.
32. Boland, C. R., Thibodeau, S. N., Hamilton, S. R., Sidransky, D., Eshleman, J. R., Burt, R. W., Meltzer, S. J., Rodriguez-Bigas, M. A., Fodde, R., Ranzani, G. N., and Srivastava, S. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res, 58: 5248-5257., 1998.
33. Chang, J. W., Chen, Y. C., Chen, C. Y., Chen, J. T., Chen, S. K., and Wang, Y. C. Correlation of genetic instability with mismatch repair protein expression and p53 mutations in non-small cell lung cancer. Clin Cancer Res, 6: 1639-1646, 2000.
34. Herzog, C. R., Devereux, T. R., Pittman, B., and You, M. Carcinogenic induction directs the selection of allelic losses in mouse lung tumorigenesis. Cancer Res, 62: 6424-6429., 2002.
35. Mertens, F., Johansson, B., Hoglund, M., and Mitelman, F. Chromosomal imbalance maps of malignant solid tumors: a cytogenetic survey of 3185 neoplasms. Cancer Res, 57: 2765-2780., 1997.
36. Gagos, S. and Irminger-Finger, I. Chromosome instability in neoplasia: chaotic roots to continuous growth. Int J Biochem Cell Biol, 37: 1014-1033., 2005.
37. Jallepalli, P. V. and Lengauer, C. Chromosome segregation and cancer: cutting through the mystery. Nat Rev Cancer, 1: 109-117., 2001.
38. Presneau, N., Manderson, E. N., and Tonin, P. N. The quest for a tumor suppressor gene phenotype. Curr Mol Med, 3: 605-629., 2003.
39. ELhamidi, A., Hamoudi, R. A., Kocjan, G., and Du, M. Q. Cervical intraepithelial neoplasia: prognosis by combined LOH analysis of multiple loci. Gynecol Oncol, 94: 671-679., 2004.
40. Bozzetti, C., Bortesi, B., and Merisio, C. Loss of heterozygosity (LOH) in ovarian cancer. Int J Gynaecol Obstet, 85: 294-295., 2004.
41. Tsuchiya, E., Nakamura, Y., Weng, S. Y., Nakagawa, K., Tsuchiya, S., Sugano, H., and Kitagawa, T. Allelotype of non-small cell lung carcinoma--comparison between loss of heterozygosity in squamous cell carcinoma and adenocarcinoma. Cancer Res, 52: 2478-2481, 1992.
42. Tomlinson, I. P., Lambros, M. B., and Roylance, R. R. Loss of heterozygosity analysis: practically and conceptually flawed? Genes Chromosomes Cancer, 34: 349-353., 2002.
43. Choi, S. W., Park, S. W., Lee, K. Y., Kim, K. M., Chung, Y. J., and Rhyu, M. G. Fractional allelic loss in gastric carcinoma correlates with growth patterns. Oncogene, 17: 2655-2659, 1998.
44. Nagai, H., Pineau, P., Tiollais, P., Buendia, M. A., and Dejean, A. Comprehensive allelotyping of human hepatocellular carcinoma. Oncogene, 14: 2927-2933, 1997.
45. Shen, C. Y., Yu, J. C., Lo, Y. L., Kuo, C. H., Yue, C. T., Jou, Y. S., Huang, C. S., Lung, J. C., and Wu, C. W. Genome-wide search for loss of heterozygosity using laser capture microdissected tissue of breast carcinoma: an implication for mutator phenotype and breast cancer pathogenesis. Cancer Res, 60: 3884-3892, 2000.
46. Yokota, J., Wada, M., Shimosato, Y., Terada, M., and Sugimura, T. Loss of heterozygosity on chromosomes 3, 13, and 17 in small-cell carcinoma and on chromosome 3 in adenocarcinoma of the lung. Proc Natl Acad Sci U S A, 84: 9252-9256, 1987.
47. Sato, S., Nakamura, Y., and Tsuchiya, E. Difference of allelotype between squamous cell carcinoma and adenocarcinoma of the lung. Cancer Res, 54: 5652-5655, 1994.
48. Shiseki, M., Kohno, T., Nishikawa, R., Sameshima, Y., Mizoguchi, H., and Yokota, J. Frequent allelic losses on chromosomes 2q, 18q, and 22q in advanced non-small cell lung carcinoma. Cancer Res, 54: 5643-5648, 1994.
49. Yokota, J., Wada, M., Shimosato, Y., Terada, M., and Sugimura, T. Loss of heterozygosity on chromosomes 3, 13, and 17 in small-cell carcinoma and on chromosome 3 in adenocarcinoma of the lung. Proc Natl Acad Sci U S A, 84: 9252-9256, 1987.
50. Weber, J. L. and May, P. E. Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. Am J Hum Genet, 44: 388-396, 1989.
51. Shiseki, M., Kohno, T., Adachi, J., Okazaki, T., Otsuka, T., Mizoguchi, H., Noguchi, M., Hirohashi, S., and Yokota, J. Comparative allelotype of early and advanced stage non-small cell lung carcinomas. Genes Chromosomes Cancer, 17: 71-77, 1996.
52. Field, J. K., Neville, E. M., Stewart, M. P., Swift, A., Liloglou, T., Risk, J. M., Ross, H., Gosney, J. R., and Donnelly, R. J. Fractional allele loss data indicate distinct genetic populations in the development of non-small-cell lung cancer. Br J Cancer, 74: 1968-1974., 1996.
53. Girard, L., Zochbauer-Muller, S., Virmani, A. K., Gazdar, A. F., and Minna, J. D. Genome-wide allelotyping of lung cancer identifies new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. Cancer Res, 60: 4894-4906, 2000.
54. Eisen, M. B. and Brown, P. O. DNA arrays for analysis of gene expression. Methods Enzymol, 303: 179-205, 1999.
55. Jou, Y. S., Lee, C. S., Chang, Y. H., Hsiao, C. F., Chen, C. F., Chao, C. C., Wu, L. S., Yeh, S. H., Chen, D. S., and Chen, P. J. Clustering of minimal deleted regions reveals distinct genetic pathways of human hepatocellular carcinoma. Cancer Res, 64: 3030-3036., 2004.
56. Chen, J. T., Chen, Y. C., Chen, C. Y., and Wang, Y. C. Loss of p16 and/or pRb protein expression in NSCLC. An immunohistochemical and prognostic study. Lung Cancer, 31: 163-170., 2001.
57. Chen, J. T., Chen, Y. C., Wang, Y. C., Tseng, R. C., and Chen, C. Y. Alterations of the p16(ink4a) gene in resected nonsmall cell lung tumors and exfoliated cells within sputum. Int J Cancer, 98: 724-731, 2002.
58. Virmani, A. K., Fong, K. M., Kodagoda, D., McIntire, D., Hung, J., Tonk, V., Minna, J. D., and Gazdar, A. F. Allelotyping demonstrates common and distinct patterns of chromosomal loss in human lung cancer types. Genes Chromosomes Cancer, 21: 308-319, 1998.
59. Gasparian, A. V., Laktionov, K. K., Belialova, M. S., Pirogova, N. A., Tatosyan, A. G., and Zborovskaya, I. B. Allelic imbalance and instability of microsatellite loci on chromosome 1p in human non-small-cell lung cancer. Br J Cancer, 77: 1604-1611, 1998.
60. Petersen, S., Aninat-Meyer, M., Schluns, K., Gellert, K., Dietel, M., and Petersen, I. Chromosomal alterations in the clonal evolution to the metastatic stage of squamous cell carcinomas of the lung. Br J Cancer, 82: 65-73, 2000.
61. Shivapurkar, N., Virmani, A. K., Wistuba, II, Milchgrub, S., Mackay, B., Minna, J. D., and Gazdar, A. F. Deletions of chromosome 4 at multiple sites are frequent in malignant mesothelioma and small cell lung carcinoma. Clin Cancer Res, 5: 17-23, 1999.
62. Wu, X., Zhao, Y., Kemp, B. L., Amos, C. I., Siciliano, M. J., and Spitz, M. R. Chromosome 5 aberrations and genetic predisposition to lung cancer. Int J Cancer, 79: 490-493., 1998.
63. Mendes-da-Silva, P., Moreira, A., Duro-da-Costa, J., Matias, D., and Monteiro, C. Frequent loss of heterozygosity on chromosome 5 in non-small cell lung carcinoma. Mol Pathol, 53: 184-187., 2000.
64. Petersen, I., Bujard, M., Petersen, S., Wolf, G., Goeze, A., Schwendel, A., Langreck, H., Gellert, K., Reichel, M., Just, K., du Manoir, S., Cremer, T., Dietel, M., and Ried, T. Patterns of chromosomal imbalances in adenocarcinoma and squamous cell carcinoma of the lung. Cancer Res, 57: 2331-2335., 1997.
65. Tommasi, S., Dammann, R., Jin, S. G., Zhang Xf, X. F., Avruch, J., and Pfeifer, G. P. RASSF3 and NORE1: identification and cloning of two human homologues of the putative tumor suppressor gene RASSF1. Oncogene, 21: 2713-2720., 2002.
66. Tsuchiya, E., Tanigami, A., Ishikawa, Y., Nishida, K., Hayashi, M., Tokuchi, Y., Hashimoto, T., Okumura, S., Tsuchiya, S., and Nakagawa, K. Three new regions on chromosome 17p13.3 distal to p53 with possible tumor suppressor gene involvement in lung cancer. Jpn J Cancer Res, 91: 589-596, 2000.
67. Sanchez-Cespedes, M., Ahrendt, S. A., Piantadosi, S., Rosell, R., Monzo, M., Wu, L., Westra, W. H., Yang, S. C., Jen, J., and Sidransky, D. Chromosomal alterations in lung adenocarcinoma from smokers and nonsmokers. Cancer Res, 61: 1309-1313, 2001.
68. Sozzi, G., Veronese, M. L., Negrini, M., Baffa, R., Cotticelli, M. G., Inoue, H., Tornielli, S., Pilotti, S., De Gregorio, L., Pastorino, U., Pierotti, M. A., Ohta, M., Huebner, K., and Croce, C. M. The FHIT gene 3p14.2 is abnormal in lung cancer. Cell, 85: 17-26., 1996.
69. Fong, K. M., Biesterveld, E. J., Virmani, A., Wistuba, I., Sekido, Y., Bader, S. A., Ahmadian, M., Ong, S. T., Rassool, F. V., Zimmerman, P. V., Giaccone, G., Gazdar, A. F., and Minna, J. D. FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. Cancer Res, 57: 2256-2267., 1997.
70. Wang, Y. C., Lu, Y. P., Tseng, R. C., Lin, R. K., Chang, J. W., Chen, J. T., Shih, C. M., and Chen, C. Y. Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples. J Clin Invest, 111: 887-895., 2003.
71. Slee, E. A., Adrain, C., and Martin, S. J. Executioner caspase-3, -6, and -7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem, 276: 7320-7326, 2001.
72. Decary, S., Decesse, J. T., Ogryzko, V., Reed, J. C., Naguibneva, I., Harel-Bellan, A., and Cremisi, C. E. The retinoblastoma protein binds the promoter of the survival gene bcl-2 and regulates its transcription in epithelial cells through transcription factor AP-2. Mol Cell Biol, 22: 7877-7888., 2002.
73. Minna, J. D., Roth, J. A., and Gazdar, A. F. Focus on lung cancer. Cancer Cell, 1: 49-52, 2002.
74. Zeid, N. A. and Muller, H. K. Tobacco smoke induced lung granulomas and tumors: association with pulmonary Langerhans cells. Pathology, 27: 247-254., 1995.
75. Hirao, T., Nelson, H. H., Ashok, T. D., Wain, J. C., Mark, E. J., Christiani, D. C., Wiencke, J. K., and Kelsey, K. T. Tobacco smoke-induced DNA damage and an early age of smoking initiation induce chromosome loss at 3p21 in lung cancer. Cancer Res, 61: 612-615, 2001.
76. Makkinje, A., Quinn, D. A., Chen, A., Cadilla, C. L., Force, T., Bonventre, J. V., and Kyriakis, J. M. Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress. J Biol Chem, 275: 17838-17847., 2000.
77. Daniels, D. L. and Weis, W. I. ICAT inhibits beta-catenin binding to Tcf/Lef-family transcription factors and the general coactivator p300 using independent structural modules. Mol Cell, 10: 573-584., 2002.
78. Tapon, N. and Hall, A. Rho, Rac and Cdc42 GTPases regulate the organization of the actin cytoskeleton. Curr Opin Cell Biol, 9: 86-92., 1997.
79. Gasparotto, D., Vukosavljevic, T., Piccinin, S., Barzan, L., Sulfaro, S., Armellin, M., Boiocchi, M., and Maestro, R. Loss of heterozygosity at 10q in tumors of the upper respiratory tract is associated with poor prognosis. Int J Cancer, 84: 432-436., 1999.
80. Siafakas, N. M., Tzortzaki, E. G., Sourvinos, G., Bouros, D., Tzanakis, N., Kafatos, A., and Spandidos, D. Microsatellite DNA instability in COPD. Chest, 116: 47-51, 1999.
81. Park, J. Y., Jeon, H. S., Park, S. H., Park, T. I., Son, J. W., Kim, C. H., Park, J. H., Kim, I. S., Jung, T. H., and Jun, S. H. Microsatellite alteration in histologically normal lung tissue of patients with non-small cell lung cancer. Lung Cancer, 30: 83-89, 2000.
82. Arvanitis, D. A., Papadakis, E., Zafiropoulos, A., and Spandidos, D. A. Fractional allele loss is a valuable marker for human lung cancer detection in sputum. Lung Cancer, 40: 55-66, 2003.
83. Chen, D. J., Marrone, B. L., Nguyen, T., Stackhouse, M., Zhao, Y., and Siciliano, M. J. Regional assignment of a human DNA repair gene (XRCC5) to 2q35 by X-ray hybrid mapping. Genomics, 21: 423-427., 1994.
84. Jeggo, P. A., Hafezparast, M., Thompson, A. F., Broughton, B. C., Kaur, G. P., Zdzienicka, M. Z., and Athwal, R. S. Localization of a DNA repair gene (XRCC5) involved in double-strand-break rejoining to human chromosome 2. Proc Natl Acad Sci U S A, 89: 6423-6427., 1992.
85. Schmitt, J. F., Millar, D. S., Pedersen, J. S., Clark, S. L., Venter, D. J., Frydenberg, M., Molloy, P. L., and Risbridger, G. P. Hypermethylation of the inhibin alpha-subunit gene in prostate carcinoma. Mol Endocrinol, 16: 213-220., 2002.
86. Richter, J., Wagner, U., Schraml, P., Maurer, R., Alund, G., Knonagel, H., Moch, H., Mihatsch, M. J., Gasser, T. C., and Sauter, G. Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer. Cancer Res, 59: 5687-5691., 1999.
87. Otsuka, T., Kohno, T., Mori, M., Noguchi, M., Hirohashi, S., and Yokota, J. Deletion mapping of chromosome 2 in human lung carcinoma. Genes Chromosomes Cancer, 16: 113-119, 1996.
88. Tseng, R. C., Chang, J. W., Hsien, F. J., Chang, Y. H., Hsiao, C. F., Chen, J. T., Chen, C. Y., Jou, Y. S., and Wang, Y. C. Genomewide loss of heterozygosity and its clinical associations in non small cell lung cancer. Int J Cancer, in press, 2005.
89. Kotsinas, A., Evangelou, K., Zacharatos, P., Kittas, C., and Gorgoulis, V. G. Proliferation, but not apoptosis, is associated with distinct beta-catenin expression patterns in non-small-cell lung carcinomas: relationship with adenomatous polyposis coli and G(1)-to S-phase cell-cycle regulators. Am J Pathol, 161: 1619-1634, 2002.
90. Nollet, F., Berx, G., Molemans, F., and van Roy, F. Genomic organization of the human beta-catenin gene (CTNNB1). Genomics, 32: 413-424, 1996.
91. Behrens, J. Control of beta-catenin signaling in tumor development. Ann N Y Acad Sci, 910: 21-33, 2000.
92. Morin, P. J. beta-catenin signaling and cancer. Bioessays, 21: 1021-1030, 1999.
93. Hommura, F., Furuuchi, K., Yamazaki, K., Ogura, S., Kinoshita, I., Shimizu, M., Moriuchi, T., Katoh, H., Nishimura, M., and Dosaka-Akita, H. Increased expression of beta-catenin predicts better prognosis in nonsmall cell lung carcinomas. Cancer, 94: 752-758, 2002.
94. Gottardi, C. J. and Gumbiner, B. M. Adhesion signaling: how beta-catenin interacts with its partners. Curr Biol, 11: R792-794, 2001.
95. Papkoff, J., Rubinfeld, B., Schryver, B., and Polakis, P. Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. Mol Cell Biol, 16: 2128-2134, 1996.
96. Nusse, R., Samos, C. H., Brink, M., Willert, K., Cadigan, K. M., Wodarz, A., Fish, M., and Rulifson, E. Cell culture and whole animal approaches to understanding signaling by Wnt proteins in Drosophila. Cold Spring Harb Symp Quant Biol, 62: 185-190, 1997.
97. Wodarz, A. and Nusse, R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol, 14: 59-88., 1998.
98. Salahshor, S. and Woodgett, J. R. The links between axin and carcinogenesis. J Clin Pathol, 58: 225-236., 2005.
99. Polakis, P. Wnt signaling and cancer. Genes Dev, 14: 1837-1851., 2000.
100. Boutros, M., Mihaly, J., Bouwmeester, T., and Mlodzik, M. Signaling specificity by Frizzled receptors in Drosophila. Science, 288: 1825-1828., 2000.
101. Morin, P. J., Sparks, A. B., Korinek, V., Barker, N., Clevers, H., Vogelstein, B., and Kinzler, K. W. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science, 275: 1787-1790., 1997.
102. Kitagawa, M., Hatakeyama, S., Shirane, M., Matsumoto, M., Ishida, N., Hattori, K., Nakamichi, I., Kikuchi, A., and Nakayama, K. An F-box protein, FWD1, mediates ubiquitin-dependent proteolysis of beta-catenin. EMBO J, 18: 2401-2410., 1999.
103. Kase, S., Sugio, K., Yamazaki, K., Okamoto, T., Yano, T., and Sugimachi, K. Expression of E-cadherin and beta-catenin in human non-small cell lung cancer and the clinical significance. Clin Cancer Res, 6: 4789-4796, 2000.
104. Retera, J. M., Leers, M. P., Sulzer, M. A., and Theunissen, P. H. The expression of beta-catenin in non-small-cell lung cancer: a clinicopathological study. J Clin Pathol, 51: 891-894., 1998.
105. Sunaga, N., Kohno, T., Kolligs, F. T., Fearon, E. R., Saito, R., and Yokota, J. Constitutive activation of the Wnt signaling pathway by CTNNB1 (beta-catenin) mutations in a subset of human lung adenocarcinoma. Genes Chromosomes Cancer, 30: 316-321., 2001.
106. Shigemitsu, K., Sekido, Y., Usami, N., Mori, S., Sato, M., Horio, Y., Hasegawa, Y., Bader, S. A., Gazdar, A. F., Minna, J. D., Hida, T., Yoshioka, H., Imaizumi, M., Ueda, Y., Takahashi, M., and Shimokata, K. Genetic alteration of the beta-catenin gene (CTNNB1) in human lung cancer and malignant mesothelioma and identification of a new 3p21.3 homozygous deletion. Oncogene, 20: 4249-4257, 2001.
107. Ueda, M., Gemmill, R. M., West, J., Winn, R., Sugita, M., Tanaka, N., Ueki, M., and Drabkin, H. A. Mutations of the beta- and gamma-catenin genes are uncommon in human lung, breast, kidney, cervical and ovarian carcinomas. Br J Cancer, 85: 64-68, 2001.
108. Aberle, H., Bauer, A., Stappert, J., Kispert, A., and Kemler, R. beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J, 16: 3797-3804, 1997.
109. Hart, M. J., de los Santos, R., Albert, I. N., Rubinfeld, B., and Polakis, P. Downregulation of beta-catenin by human Axin and its association with the APC tumor suppressor, beta-catenin and GSK3 beta. Curr Biol, 8: 573-581., 1998.
110. Winston, J. T., Strack, P., Beer-Romero, P., Chu, C. Y., Elledge, S. J., and Harper, J. W. The SCFbeta-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IkappaBalpha and beta-catenin and stimulates IkappaBalpha ubiquitination in vitro. Genes Dev, 13: 270-283., 1999.
111. Behrens, J., Jerchow, B. A., Wurtele, M., Grimm, J., Asbrand, C., Wirtz, R., Kuhl, M., Wedlich, D., and Birchmeier, W. Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta. Science, 280: 596-599, 1998.
112. Dong, X., Seelan, R. S., Qian, C., Mai, M., and Liu, W. Genomic structure, chromosome mapping and expression analysis of the human AXIN2 gene. Cytogenet Cell Genet, 93: 26-28, 2001.
113. Mai, M., Qian, C., Yokomizo, A., Smith, D. I., and Liu, W. Cloning of the human homolog of conductin (AXIN2), a gene mapping to chromosome 17q23-q24. Genomics, 55: 341-344, 1999.
114. Rubinfeld, B., Robbins, P., El-Gamil, M., Albert, I., Porfiri, E., and Polakis, P. Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science, 275: 1790-1792, 1997.
115. Ikeda, S., Kishida, S., Yamamoto, H., Murai, H., Koyama, S., and Kikuchi, A. Axin, a negative regulator of the Wnt signaling pathway, forms a complex with GSK-3beta and beta-catenin and promotes GSK-3beta-dependent phosphorylation of beta-catenin. EMBO J, 17: 1371-1384, 1998.
116. Anderson, C. B., Neufeld, K. L., and White, R. L. Subcellular distribution of Wnt pathway proteins in normal and neoplastic colon. Proc Natl Acad Sci U S A, 99: 8683-8688, 2002.
117. Hershko, A. and Ciechanover, A. The ubiquitin system. Annu Rev Biochem, 67: 425-479, 1998.
118. Fuchs, S. Y. The role of ubiquitin-proteasome pathway in oncogenic signaling. Cancer Biol Ther, 1: 337-341, 2002.
119. Nakayama, K., Hatakeyama, S., Maruyama, S., Kikuchi, A., Onoe, K., Good, R. A., and Nakayama, K. I. Impaired degradation of inhibitory subunit of NF-kappa B (I kappa B) and beta-catenin as a result of targeted disruption of the beta-TrCP1 gene. Proc Natl Acad Sci U S A, 100: 8752-8757, 2003.
120. Wu, G., Xu, G., Schulman, B. A., Jeffrey, P. D., Harper, J. W., and Pavletich, N. P. Structure of a beta-TrCP1-Skp1-beta-catenin complex: destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase. Mol Cell, 11: 1445-1456, 2003.
121. Fuchs, S. Y., Spiegelman, V. S., and Kumar, K. G. The many faces of beta-TrCP E3 ubiquitin ligases: reflections in the magic mirror of cancer. Oncogene, 23: 2028-2036, 2004.
122. Fujiwara, T., Suzuki, M., Tanigami, A., Ikenoue, T., Omata, M., Chiba, T., and Tanaka, K. The BTRC gene, encoding a human F-box/WD40-repeat protein, maps to chromosome 10q24-q25. Genomics, 58: 104-105., 1999.
123. Yaron, A., Hatzubai, A., Davis, M., Lavon, I., Amit, S., Manning, A. M., Andersen, J. S., Mann, M., Mercurio, F., and Ben-Neriah, Y. Identification of the receptor component of the IkappaBalpha-ubiquitin ligase. Nature, 396: 590-594, 1998.
124. Kudo, Y., Guardavaccaro, D., Santamaria, P. G., Koyama-Nasu, R., Latres, E., Bronson, R., Yamasaki, L., and Pagano, M. Role of F-box protein betaTrcp1 in mammary gland development and tumorigenesis. Mol Cell Biol, 24: 8184-8194, 2004.
125. Deshaies, R. J. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu Rev Cell Dev Biol, 15: 435-467, 1999.
126. Guardavaccaro, D., Kudo, Y., Boulaire, J., Barchi, M., Busino, L., Donzelli, M., Margottin-Goguet, F., Jackson, P. K., Yamasaki, L., and Pagano, M. Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo. Dev Cell, 4: 799-812, 2003.
127. Bour, S., Perrin, C., Akari, H., and Strebel, K. The human immunodeficiency virus type 1 Vpu protein inhibits NF-kappa B activation by interfering with beta TrCP-mediated degradation of Ikappa B. J Biol Chem, 276: 15920-15928, 2001.
128. Fuchs, S. Y., Chen, A., Xiong, Y., Pan, Z. Q., and Ronai, Z. HOS, a human homolog of Slimb, forms an SCF complex with Skp1 and Cullin1 and targets the phosphorylation-dependent degradation of IkappaB and beta-catenin. Oncogene, 18: 2039-2046, 1999.
129. Lassot, I., Segeral, E., Berlioz-Torrent, C., Durand, H., Groussin, L., Hai, T., Benarous, R., and Margottin-Goguet, F. ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. Mol Cell Biol, 21: 2192-2202, 2001.
130. Roose, J. and Clevers, H. TCF transcription factors: molecular switches in carcinogenesis. Biochim Biophys Acta, 1424: M23-37, 1999.
131. Graham, T. A., Clements, W. K., Kimelman, D., and Xu, W. The crystal structure of the beta-catenin/ICAT complex reveals the inhibitory mechanism of ICAT. Mol Cell, 10: 563-571, 2002.
132. Sekiya, T., Nakamura, T., Kazuki, Y., Oshimura, M., Kohu, K., Tago, K., Ohwada, S., and Akiyama, T. Overexpression of Icat induces G(2) arrest and cell death in tumor cell mutants for adenomatous polyposis coli, beta-catenin, or Axin. Cancer Res, 62: 3322-3326, 2002.
133. Tago, K., Nakamura, T., Nishita, M., Hyodo, J., Nagai, S., Murata, Y., Adachi, S., Ohwada, S., Morishita, Y., Shibuya, H., and Akiyama, T. Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein. Genes Dev, 14: 1741-1749., 2000.
134. Stow, J. L. ICAT is a multipotent inhibitor of beta-catenin. Focus on "role for ICAT in beta-catenin-dependent nuclear signaling and cadherin functions". Am J Physiol Cell Physiol, 286: C745-746, 2004.
135. Katoh, M. Molecular cloning and characterization of LZIC, a novel gene encoding ICAT homologous protein with leucine zipper domain. Int J Mol Med, 8: 611-615, 2001.
136. Koyama, T., Tago, K., Nakamura, T., Ohwada, S., Morishita, Y., Yokota, J., and Akiyama, T. Mutation and expression of the beta-catenin-interacting protein ICAT in human colorectal tumors. Jpn J Clin Oncol, 32: 358-362, 2002.
137. Gottardi, C. J. and Gumbiner, B. M. Role for ICAT in beta-catenin-dependent nuclear signaling and cadherin functions. Am J Physiol Cell Physiol, 286: C747-756, 2004.
138. Liu, W., Dong, X., Mai, M., Seelan, R. S., Taniguchi, K., Krishnadath, K. K., Halling, K. C., Cunningham, J. M., Boardman, L. A., Qian, C., Christensen, E., Schmidt, S. S., Roche, P. C., Smith, D. I., and Thibodeau, S. N. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signalling. Nat Genet, 26: 146-147., 2000.
139. Lammi, L., Arte, S., Somer, M., Jarvinen, H., Lahermo, P., Thesleff, I., Pirinen, S., and Nieminen, P. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet, 74: 1043-1050, 2004.
140. Ishizaki, Y., Ikeda, S., Fujimori, M., Shimizu, Y., Kurihara, T., Itamoto, T., Kikuchi, A., Okajima, M., and Asahara, T. Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas. Int J Oncol, 24: 1077-1083, 2004.
141. Wu, R., Zhai, Y., Fearon, E. R., and Cho, K. R. Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas. Cancer Res, 61: 8247-8255, 2001.
142. Moreno-Bueno, G., Hardisson, D., Sanchez, C., Sarrio, D., Cassia, R., Garcia-Rostan, G., Prat, J., Guo, M., Herman, J. G., Matias-Guiu, X., Esteller, M., and Palacios, J. Abnormalities of the APC/beta-catenin pathway in endometrial cancer. Oncogene, 21: 7981-7990, 2002.
143. Doglioni, C., Piccinin, S., Demontis, S., Cangi, M. G., Pecciarini, L., Chiarelli, C., Armellin, M., Vukosavljevic, T., Boiocchi, M., and Maestro, R. Alterations of beta-catenin pathway in non-melanoma skin tumors: loss of alpha-ABC nuclear reactivity correlates with the presence of beta-catenin gene mutation. Am J Pathol, 163: 2277-2287, 2003.
144. Yan, D., Wiesmann, M., Rohan, M., Chan, V., Jefferson, A. B., Guo, L., Sakamoto, D., Caothien, R. H., Fuller, J. H., Reinhard, C., Garcia, P. D., Randazzo, F. M., Escobedo, J., Fantl, W. J., and Williams, L. T. Elevated expression of axin2 and hnkd mRNA provides evidence that Wnt/beta -catenin signaling is activated in human colon tumors. Proc Natl Acad Sci U S A, 98: 14973-14978., 2001.
145. Lustig, B., Jerchow, B., Sachs, M., Weiler, S., Pietsch, T., Karsten, U., van de Wetering, M., Clevers, H., Schlag, P. M., Birchmeier, W., and Behrens, J. Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol, 22: 1184-1193., 2002.
146. Spiegelman, V. S., Slaga, T. J., Pagano, M., Minamoto, T., Ronai, Z., and Fuchs, S. Y. Wnt/beta-catenin signaling induces the expression and activity of betaTrCP ubiquitin ligase receptor. Mol Cell, 5: 877-882, 2000.
147. Ougolkov, A., Zhang, B., Yamashita, K., Bilim, V., Mai, M., Fuchs, S. Y., and Minamoto, T. Associations among beta-TrCP, an E3 ubiquitin ligase receptor, beta-catenin, and NF-kappaB in colorectal cancer. J Natl Cancer Inst, 96: 1161-1170, 2004.
148. Chiaur, D. S., Murthy, S., Cenciarelli, C., Parks, W., Loda, M., Inghirami, G., Demetrick, D., and Pagano, M. Five human genes encoding F-box proteins: chromosome mapping and analysis in human tumors. Cytogenet Cell Genet, 88: 255-258, 2000.
149. Saitoh, T. and Katoh, M. Expression profiles of betaTRCP1 and betaTRCP2, and mutation analysis of betaTRCP2 in gastric cancer. Int J Oncol, 18: 959-964, 2001.
150. Reifenberger, J., Knobbe, C. B., Wolter, M., Blaschke, B., Schulte, K. W., Pietsch, T., Ruzicka, T., and Reifenberger, G. Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC. Int J Cancer, 100: 549-556, 2002.
151. Wolter, M., Scharwachter, C., Reifenberger, J., Koch, A., Pietsch, T., and Reifenberger, G. Absence of detectable alterations in the putative tumor suppressor gene BTRC in cerebellar medulloblastomas and cutaneous basal cell carcinomas. Acta Neuropathol (Berl), 106: 287-290, 2003.
152. Gerstein, A. V., Almeida, T. A., Zhao, G., Chess, E., Shih Ie, M., Buhler, K., Pienta, K., Rubin, M. A., Vessella, R., and Papadopoulos, N. APC/CTNNB1 (beta-catenin) pathway alterations in human prostate cancers. Genes Chromosomes Cancer, 34: 9-16, 2002.
153. He, N., Li, C., Zhang, X., Sheng, T., Chi, S., Chen, K., Wang, Q., Vertrees, R., Logrono, R., and Xie, J. Regulation of lung cancer cell growth and invasiveness by beta-TRCP. Mol Carcinog, 42: 18-28., 2005.
154. Imai, M., Nakamura, T., Akiyama, T., and Horii, A. Infrequent somatic mutations of the ICAT gene in various human cancers with frequent 1p-LOH and/or abnormal nuclear accumulation of beta-catenin. Oncol Rep, 12: 1099-1103, 2004.
155. Hsu, H. S., Wang, Y. C., Tseng, R. C., Chang, J. W., Chen, J. T., Shih, C. M., and Chen, C. Y. 5' cytosine-phospho-guanine island methylation is responsible for p14ARF inactivation and inversely correlates with p53 overexpression in resected non-small cell lung cancer. Clin Cancer Res, 10: 4734-4741., 2004.
156. Ushijima, T. Detection and interpretation of altered methylation patterns in cancer cells. Nat Rev Cancer, 5: 223-231., 2005.
157. Iwaya, K., Ogawa, H., Kuroda, M., Izumi, M., Ishida, T., and Mukai, K. Cytoplasmic and/or nuclear staining of beta-catenin is associated with lung metastasis. Clin Exp Metastasis, 20: 525-529., 2003.
158. Koch, A., Weber, N., Waha, A., Hartmann, W., Denkhaus, D., Behrens, J., Birchmeier, W., von Schweinitz, D., and Pietsch, T. Mutations and elevated transcriptional activity of conductin (AXIN2) in hepatoblastomas. J Pathol, 204: 546-554., 2004.
159. Taniguchi, K., Roberts, L. R., Aderca, I. N., Dong, X., Qian, C., Murphy, L. M., Nagorney, D. M., Burgart, L. J., Roche, P. C., Smith, D. I., Ross, J. A., and Liu, W. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene, 21: 4863-4871., 2002.
160. Liu, C., Kato, Y., Zhang, Z., Do, V. M., Yankner, B. A., and He, X. beta-Trcp couples beta-catenin phosphorylation-degradation and regulates Xenopus axis formation. Proc Natl Acad Sci U S A, 96: 6273-6278, 1999.
161. Ballarino, M., Marchioni, M., and Carnevali, F. The Xenopus laevis beta TrCP gene: genomic organization, alternative splicing, 5' and 3' region characterization and comparison of its structure with that of human beta TrCP genes. Biochim Biophys Acta, 1577: 81-92., 2002.
162. Schwarzacher, T. DNA, chromosomes, and in situ hybridization. Genome, 46: 953-962, 2003.
163. Gray, J. W. and Collins, C. Genome changes and gene expression in human solid tumors. Carcinogenesis, 21: 443-452, 2000.
164. Vogelstein, B., Fearon, E. R., Hamilton, S. R., Kern, S. E., Preisinger, A. C., Leppert, M., Nakamura, Y., White, R., Smits, A. M., and Bos, J. L. Genetic alterations during colorectal-tumor development. N Engl J Med, 319: 525-532, 1988.
165. Lasko, D., Cavenee, W., and Nordenskjold, M. Loss of constitutional heterozygosity in human cancer. Annu Rev Genet, 25: 281-314, 1991.
166. Yokota, J. and Sugimura, T. Multiple steps in carcinogenesis involving alterations of multiple tumor suppressor genes. FASEB J, 7: 920-925, 1993.
167. Thiagalingam, S., Foy, R. L., Cheng, K. H., Lee, H. J., Thiagalingam, A., and Ponte, J. F. Loss of heterozygosity as a predictor to map tumor suppressor genes in cancer: molecular basis of its occurrence. Curr Opin Oncol, 14: 65-72, 2002.
168. Altschul, S. F., Gish, W., Miller, W., Myers, E. W., and Lipman, D. J. Basic local alignment search tool. J Mol Biol, 215: 403-410, 1990.
169. Gish, W. and States, D. J. Identification of protein coding regions by database similarity search. Nat Genet, 3: 266-272, 1993.
170. Protopopov, A., Kashuba, V., Zabarovska, V. I., Muravenko, O. V., Lerman, M. I., Klein, G., and Zabarovsky, E. R. An integrated physical and gene map of the 3.5-Mb chromosome 3p21.3 (AP20) region implicated in major human epithelial malignancies. Cancer Res, 63: 404-412, 2003.
171. Blobel, C. P., Wolfsberg, T. G., Turck, C. W., Myles, D. G., Primakoff, P., and White, J. M. A potential fusion peptide and an integrin ligand domain in a protein active in sperm-egg fusion. Nature, 356: 248-252, 1992.
172. Wolfsberg, T. G., Primakoff, P., Myles, D. G., and White, J. M. ADAM, a novel family of membrane proteins containing A Disintegrin And Metalloprotease domain: multipotential functions in cell-cell and cell-matrix interactions. J Cell Biol, 131: 275-278, 1995.
173. Millichip, M. I., Dallas, D. J., Wu, E., Dale, S., and McKie, N. The metallo-disintegrin ADAM10 (MADM) from bovine kidney has type IV collagenase activity in vitro. Biochem Biophys Res Commun, 245: 594-598, 1998.
174. Blobel, C. P. Metalloprotease-disintegrins: links to cell adhesion and cleavage of TNF alpha and Notch. Cell, 90: 589-592, 1997.
175. Stone, A. L., Kroeger, M., and Sang, Q. X. Structure-function analysis of the ADAM family of disintegrin-like and metalloproteinase-containing proteins. J Protein Chem, 18: 447-465, 1999.
176. van der Velden, V. H. and Hulsmann, A. R. Peptidases: structure, function and modulation of peptide-mediated effects in the human lung. Clin Exp Allergy, 29: 445-456, 1999.
177. Curran, S. and Murray, G. I. Matrix metalloproteinases: molecular aspects of their roles in tumor invasion and metastasis. Eur J Cancer, 36: 1621-1630, 2000.
178. Kerr, K. M., MacKenzie, S. J., Ramasami, S., Murray, G. I., Fyfe, N., Chapman, A. D., Nicolson, M. C., and King, G. Expression of Fhit, cell adhesion molecules and matrix metalloproteinases in atypical adenomatous hyperplasia and pulmonary adenocarcinoma. J Pathol, 203: 638-644, 2004.
179. Emi, M., Katagiri, T., Harada, Y., Saito, H., Inazawa, J., Ito, I., Kasumi, F., and Nakamura, Y. A novel metalloprotease/disintegrin-like gene at 17q21.3 is somatically rearranged in two primary breast cancers. Nat Genet, 5: 151-157, 1993.
180. Scherf, M., Klingenhoff, A., and Werner, T. Highly specific localization of promoter regions in large genomic sequences by PromoterInspector: a novel context analysis approach. J Mol Biol, 297: 599-606, 2000.
181. Fickett, J. W. and Hatzigeorgiou, A. G. Eukaryotic promoter recognition. Genome Res, 7: 861-878, 1997.
182. Jean, D., Guillaume, N., and Frade, R. Characterization of human cathepsin L promoter and identification of binding sites for NF-Y, Sp1 and Sp3 that are essential for its activity. Biochem J, 361: 173-184, 2002.
183. Borkakoti, N. Structural studies of matrix metalloproteinases. J Mol Med, 78: 261-268, 2000.
184. Shipp, M. A., Tarr, G. E., Chen, C. Y., Switzer, S. N., Hersh, L. B., Stein, H., Sunday, M. E., and Reinherz, E. L. CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung. Proc Natl Acad Sci U S A, 88: 10662-10666, 1991.