進階搜尋


下載電子全文  
系統識別號 U0026-0208201100402000
論文名稱(中文) 食道鱗狀上皮細胞癌疾病預後之DNA甲基化分子指標鑑定與候選抑癌基因SOX17之研究
論文名稱(英文) Identification of DNA Methylation Biomarkers for Prognosis Prediction and Characterization of Candidate Tumor Suppressor Gene SOX17 in Esophageal Squamous Cell Carcinoma
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 99
學期 2
出版年 100
研究生(中文) 吳靜琪
研究生(英文) Ching-Chi Wu
學號 S26984090
學位類別 碩士
語文別 英文
論文頁數 102頁
口試委員 指導教授-王憶卿
口試委員-呂佩融
口試委員-劉校生
中文關鍵字 食道鱗狀上皮細胞癌  DNA甲基化分子指標 
英文關鍵字 Esophageal Squamous Cell Carcinoma  DNA Methylation Biomarkers  SOX17 
學科別分類
中文摘要 背景: 食道癌是國人男性癌症死亡原因的第六位,其五年存活率不到20%。食道癌的高死亡率主要是由於早期診斷不易及治療後的高復發率所致。過去研究顯示許多分子層次的改變參與癌症的形成及惡化,已證實在食道癌細胞之許多抑癌基因有啟動子過度甲基化(promoter hypermethylation)的情形,而且這些抑癌基因之啟動子過度甲基化與食道癌患者的不良預後(poor prognosis)有關。
研究目的: 本研究首先建立食道癌全基因體DNA甲基化異常圖譜,以鑑定出預測食道癌患者存活率預後的甲基化分子指標,繼而從中挑選新穎的抑癌基因SOX17作進一步的分子致癌機制研究。
研究方法與結果:首先利用甲基化晶片(Illumina GoldenGate methylation assay)做為DNA甲基化圖譜的平台,並利用Prediction Analysis for Microarray 統計方法挑選出28個與疾病預後相關的探針(probes),接著利用pyrosequencing 進行驗證,顯示其中五個探針的甲基化程度在腫瘤組織明顯高於鄰近周圍的正常組織(P<0.0001~P=0.037);也利用資料整合型分析(Level-based-mining method) 挑選10個與疾病存活率相關的基因。進一步,從中挑選了在兩種不同分析平台中重複出現的新穎抑癌基因- SOX17 [SRY (sex determining region Y)-box 17] 以臨床病人、細胞、動物模式進行分子致癌機制研究。藉由pyrosequencing 驗證有 40.3% (29/72) 食道癌病人SOX17基因啟動子過度甲基化,進一步,利用定量RT-PCR (quantitative reverse transcription polymerase chain reaction, qRT-PCR) 和免疫組織染色(immunohistochemistry)分析病人SOX17表達量,發現食道癌病人中SOX17 mRNA 及蛋白分別有 40.3% (29/72) 及 47.4% (73/154) 低表現。而且發現 SOX17 啟動子過度甲基化或蛋白低表現的食道癌病人其疾病預後較差(P值分別為0.01和小於0.0001);此外,在病人檢體中,發現SOX17過度甲基化程度與其mRNA 及蛋白表現呈現負相關(P值分別為0.016和小於0.001)。在細胞層次,給予癌細胞去甲基化藥物5’-aza-dC後,SOX17表現量上升,證實 SOX17 低表現的確是因為啟動子過度甲基化所造成。進一步,在食道癌細胞中探討 SOX17 的生物功能,分別利用細胞存活率實驗(MTT assay)、細胞群落生長實驗(colony formation assay)、細胞爬行移動力實驗 (wound healing assay 及 transwell-migration assay)、細胞侵略移動力實驗(invasion assay) 觀察SOX17在癌細胞中恢復表現對細胞生長及細胞移動能力的影響,發現SOX17恢復表現不會抑制癌細胞生長,但會抑制癌細胞群落生長、爬行及侵略能力。為了深入探討SOX17抑癌機制,發現SOX17可能是透過減少其下游與細胞增生及爬行能力相關基因(如: CyclinD 1和MET),及交互作用蛋白b-catenin的表現量,進而達到抑制細胞群落生長及爬行能力。進一步,為了尋找SOX17調控轉錄的新穎目標基因,以表現圖譜(expression array)與路徑分析(pathway analyses),發現受SOX17所調控的基因中,有20%的基因參與調控細胞骨架(cytoskeleton remodeling)及11%的基因參與調控細胞貼附(cell adhesion)。其中許多已知會促使癌細胞轉移的基因可被SOX17調控而表現量下降。
結論: 本研究建立食道癌全基因體異常甲基化圖譜,並鑑定得到5個與食道癌疾病預後相關的甲基化候選基因。抑癌基因SOX17過度甲基化是個相當有潛力的食道癌疾病預後分子指標,其在抑制食道癌腫瘤生成或癌細胞轉移過程中扮演著重要角色,這些角色正在食道癌動物模式中驗證。未來,將建立SOX17調控的轉錄目標基因的連絡網,進而探討食道癌形成與進展機制。
英文摘要 Background: The five-year survival rate is less than 20% for esophageal squamous cell carcinoma (ESCC). The poor prognosis is particularly due to the difficulties in early diagnosis and high rate of cancer recurrence. In addition, promoter hypermethylation of tumor suppressor genes correlates with cancer formation and poor prognosis of ESCC.
Purpose: This study aims to identify DNA methylation biomarkers for prognosis prediction of ESCC patients and investigate candidate tumor suppressor gene SOX17 in ESCC cell, animal, and clinical models.
Methods and Results: Genome-wide methylation analysis was performed by Illumina GoldenGate methylation assay. Two analysis methods were used to select candidate methylated genes. First method was Prediction Analysis for Microarrays and 28 probes with prognostic potential were identified. Five of 28 probes were validated by Kaplan-Meier method and pyrosequencing assay to show that hypermethylated probes correlated with poor prognosis of ESCC patients (P=0.004~P=0.083). Second method was Level-based-mining method and 10 cancer-related survivability genes were selected. We further studied a candidate tumor suppressor gene with prognostic potential in both methods, SRY (sex determining region Y)-box 17 (SOX17). Pyrosequencing results showed that 40.3% (29/72) of ESCC patients exhibited SOX17 hypermethylation. Quantitative RT-PCR and immunohistochemistry data showed that 40.3% (29/72) and 47.4% (73/154) of ESCC patients had SOX17 mRNA and protein low expression, respectively. Patients with hypermethylated (P=0.011) or low protein expression (P<0.00001) of SOX17 showed poor prognosis. Importantly, we found an inverse correlation of SOX17 hypermethylation to mRNA expression (P=0.016) and protein expression (P<0.001) in ESCC patients, and restoration of SOX17 expression was observed in ESCC cell lines after treatment with demethyaltion agent 5'-aza-dC, suggesting that DNA hypermethylation could be a predominant mechanism responsible for SOX17 low expression. Furthermore, using MTT assay, colony formation assay, would healing assay, transwell migration and invasion assay, we found that SOX17 overexpression did not reduce cancer cell proliferation, but decreased colony formation, migration and invasion abilities of ESCC cells. The reduced mRNA and protein expressions of downstream genes Cyclin D1 and MET, and low level of SOX17 interacting protein b-catenin were observed in SOX17 overexpression cells. In addition, we performed expression array analyses to identify more novel transcriptional target genes of SOX17. The pathway analyses showed that 20% of the SOX17 regulated genes were involved in cell remodeling and 11% genes were in cell adhesion. Interestingly, several putative target genes were down-regulated by SOX17 overexpression, which have been shown to promote cell migration.
Conclusions: This study established ESCC genome-wide methylation database with five genes validated. We will verify more candidate methylated genes with prognostic potential in the future. Our study shows for the first time that loss of one validated gene, SOX17, plays a key role in prognosis of ESCC patients, and SOX17 is a tumor suppressor in suppressing ESCC cell anchorage-independent growth, migration and invasion ability. The tumor growth suppression roles of SOX17 are under investigation in ESCC xenograft animal models. Establishment of SOX17 regulated genes network is ongoing to further investigate the mechanism of ESCC tumorigenesis and metastasis.
論文目次 Introduction 1
I. The clinical significance of esophageal cancer in Taiwan 1
(a) The unique clinical and epidemiological characteristics of esophageal cancer in Taiwan 1
(b) Current diagnostic tools and therapeutic approaches of esophageal cancer 2
II. The molecular alterations and molecular diagnostic markers in ESCC 3
(a) Genetic alterations and known biomarker candidate genes in ESCC cancers 3
(b) Epigenetic alterations in ESCC cancers 4
(c) Known DNA hypermethylation candidate biomarkers in ESCC 6
III. Overview of SOX family and SOX17 gene 7
(a) The characteristics of SOX family 7
(b) Overview of SOX17 gene 8
(c) The role of SOX17 in Wnt signaling pathway and its tumor suppressive mechanism 9
(d) Molecular alterations of SOX17 in cancers 10
Study Basis and Specific Aims 12
Materials and Methods 13
I. Clinical samples of ESCC patients 13
II. Cell lines and culture 13
III. Genomic DNA extraction and sodium bisulfite conversion 14
IV. The Genome-wide methylation analysis platforms 14
V. Pyrosequencing assay 15
VI. RNA extraction and quantitative reverse transcription-PCR 16
VII. Immunohistochemistry (IHC) staining 16
VIII. 5-aza-2’-deoxycitidine (5-aza-dC) treatment 17
IX. Expression vector constructs and transfection 17
X. Western blot analysis 18
XI. MTT assay 19
XII. Colony formation assay 19
XIII. Wound healing assay 19
XIV. Transwell migration and invasion assays 20
XV. Expression array analysis 20
XVI. Anti-tumor growth study in animal model 21
XVII. Biological software analysis 22
XVIII. Statistical analysis 22
Results 23
I. DNA methylation biomarkers study 23
(a) Genome-wide methylation study by Illumina GoldenGate technique 23
(b) Identification of 28 prognosis related probes by Prediction Analysis for Microarrays (PAM) 24
(c) Identification of 10 cancer-related survivability genes by Level-based-mining method 25
(d) Validation of candidate methylated probes with prognostic potential by Kaplan-Meier survival curves 25
(e) Concordance between methylation level measured by Illumina GoldenGate technique and pyrosequencing assay 26
(f) Identification of candidate tumor suppressor gene SOX17 with prognostic potential 26
II. SXO17 study in clinical models 27
(a) SOX17 gene is frequently hypermethylated in ESCC patients 27
(b) SOX17 mRNA and protein are frequently low expression in ESCC patients 28
(c) A significant inverse correlation between DNA methylation and mRNA expression, as well as protein expression 29
(d) Patients with SOX17 DNA hypermethylation or low SOX17 protein expression show poor prognosis 29
III. SXO17 study in cell model 30
(a) SOX17 is hypermethylated and SOX17 mRNA and protein are down-regulated in ESCC cell lines 30
(b) Restoration of SOX17 expression through treatment with demethylation reagent 5-aza-dC 30
(c) SOX17 overexpression decreases colony formation ability of ESCC cells 31
(d) SOX17 overexpression decreases cancer cell migration and invasion 31
(e) SOX17 overexpression decreases expression of downstream genes in Wnt signaling pathway 32
(f) SOX17 overexpression decreases mRNA expression of genes other than Wnt signaling pathway 33
IV. SXO17 study in animal model 34
SOX17 overexpression decreases tumor growth in vivo 34
Discussion 35
References 43
Tables 51
Figures 63
Appendix tables and figures 89
參考文獻 Antequera, F., and Bird, A. (1993). Number of CpG islands and genes in human and mouse. Proc Natl Acad Sci U S A 90, 11995-11999.
Belinsky, S.A. (2004). Gene-promoter hypermethylation as a biomarker in lung cancer. Nat Rev Cancer 4, 707-717.
Bennett, K.L., Karpenko, M., Lin, M.T., Claus, R., Arab, K., Dyckhoff, G., Plinkert, P., Herpel, E., Smiraglia, D., and Plass, C. (2008). Frequently methylated tumor suppressor genes in head and neck squamous cell carcinoma. Cancer Res 68, 4494-4499.
Bernard, P., and Harley, V.R. (2010). Acquisition of SOX transcription factor specificity through protein-protein interaction, modulation of Wnt signalling and post-translational modification. Int J Biochem Cell Biol 42, 400-410.
Bibikova, M., Lin, Z., Zhou, L., Chudin, E., Garcia, E.W., Wu, B., Doucet, D., Thomas, N.J., Wang, Y., Vollmer, E., Goldmann, T., Seifart, C., Jiang, W., Barker, D.L., Chee, M.S., Floros, J., and Fan, J.B. (2006). High-throughput DNA methylation profiling using universal bead arrays. Genome Res 16, 383-393.
Bolden, J.E., Peart, M.J., and Johnstone, R.W. (2006). Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 5, 769-784.
Bowles, J., Schepers, G., and Koopman, P. (2000). Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. Dev Biol 227, 239-255.
Brandeis, M., Frank, D., Keshet, I., Siegfried, Z., Mendelsohn, M., Nemes, A., Temper, V., Razin, A., and Cedar, H. (1994). Sp1 elements protect a CpG island from de novo methylation. Nature 371, 435-438.
Brock, M.V., Gou, M., Akiyama, Y., Muller, A., Wu, T.T., Montgomery, E., Deasel, M., Germonpre, P., Rubinson, L., Heitmiller, R.F., Yang, S.C., Forastiere, A.A., Baylin, S.B., and Herman, J.G. (2003). Prognostic importance of promoter hypermethylation of multiple genes in esophageal adenocarcinoma. Clin Cancer Res 9, 2912-2919.
Chan, S.L., Cui, Y., van Hasselt, A., Li, H., Srivastava, G., Jin, H., Ng, K.M., Wang, Y., Lee, K.Y., Tsao, G.S., Zhong, S., Robertson, K.D., Rha, S.Y., Chan, A.T., and Tao, Q. (2007). The tumor suppressor Wnt inhibitory factor 1 is frequently methylated in nasopharyngeal and esophageal carcinomas. Lab Invest 87, 644-650.
Chen, X., Hu, H., Guan, X., Xiong, G., Wang, Y., Wang, K., Li, J., Xu, X., Yang, K., and Bai, Y. (2011a). CpG island methylation status of miRNAs in esophageal squamous cell carcinoma. Int J Cancer. on-line publication
Chen, Z.L., Zhao, X.H., Wang, J.W., Li, B.Z., Wang, Z., Sun, J., Tan, F.W., Ding, D.P., Xu, X.H., Zhou, F., Tan, X.G., Hang, J., Shi, S.S., Feng, X.L., and He, J. (2011b). microRNA-92a promotes lymph node metastasis of human esophageal squamous cell carcinoma via E-cadherin. J Biol Chem 286, 10725-10734.
Chien, A.J., Conrad, W.H., and Moon, R.T. (2009). A Wnt survival guide: from flies to human disease. J Invest Dermatol 129, 1614-1627.
Costello, J.F., Fruhwald, M.C., Smiraglia, D.J., Rush, L.J., Robertson, G.P., Gao, X., Wright, F.A., Feramisco, J.D., Peltomaki, P., Lang, J.C., Schuller, D.E., Yu, L., Bloomfield, C.D., Caligiuri, M.A., Yates, A., Nishikawa, R., Su Huang, H., Petrelli, N.J., Zhang, X., O'Dorisio, M.S., et al. (2000). Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 24, 132-138.
De Smet, C., Lurquin, C., Lethe, B., Martelange, V., and Boon, T. (1999). DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter. Mol Cell Biol 19, 7327-7335.
Dennis, G., Jr., Sherman, B.T., Hosack, D.A., Yang, J., Gao, W., Lane, H.C., and Lempicki, R.A. (2003). DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 4, P3.
Department of Health, T.E.Y., Republic of China 2010. General Health Statistics.
Du, Y.C., Oshima, H., Oguma, K., Kitamura, T., Itadani, H., Fujimura, T., Piao, Y.S., Yoshimoto, T., Minamoto, T., Kotani, H., Taketo, M.M., and Oshima, M. (2009). Induction and down-regulation of Sox17 and its possible roles during the course of gastrointestinal tumorigenesis. Gastroenterology 137, 1346-1357.
Egger, G., Liang, G., Aparicio, A., and Jones, P.A. (2004). Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457-463.
Enzinger, P.C., and Mayer, R.J. (2003). Esophageal cancer. N Engl J Med 349, 2241-2252.
Fan, J.B., Gunderson, K.L., Bibikova, M., Yeakley, J.M., Chen, J., Wickham Garcia, E., Lebruska, L.L., Laurent, M., Shen, R., and Barker, D. (2006). Illumina universal bead arrays. Methods Enzymol 410, 57-73.
Farias, E.F., Petrie, K., Leibovitch, B., Murtagh, J., Chornet, M.B., Schenk, T., Zelent, A., and Waxman, S. (2010). Interference with Sin3 function induces epigenetic reprogramming and differentiation in breast cancer cells. Proc Natl Acad Sci U S A 107, 11811-11816.
Fu, D.Y., Wang, Z.M., Li, C., Wang, B.L., Shen, Z.Z., Huang, W., and Shao, Z.M. (2010). Sox17, the canonical Wnt antagonist, is epigenetically inactivated by promoter methylation in human breast cancer. Breast Cancer Res Treat 119, 601-612.
Fujiwara, S., Noguchi, T., Takeno, S., Kimura, Y., Fumoto, S., and Kawahara, K. (2008). Hypermethylation of p16 gene promoter correlates with loss of p16 expression that results in poorer prognosis in esophageal squamous cell carcinomas. Dis Esophagus 21, 125-131.
Galimi, F., Torti, D., Sassi, F., Isella, C., Cora, D., Gastaldi, S., Ribero, D., Muratore, A., Massucco, P., Siatis, D., Paraluppi, G., Gonella, F., Maione, F., Pisacane, A., David, E., Torchio, B., Risio, M., Salizzoni, M., Capussotti, L., Perera, T., et al. (2011). Genetic and expression analysis of MET, MACC1, and HGF in metastatic colorectal cancer: response to met inhibition in patient xenografts and pathologic correlations. Clin Cancer Res 17, 3146-3156.
Garinis, G.A., Patrinos, G.P., Spanakis, N.E., and Menounos, P.G. (2002). DNA hypermethylation: when tumour suppressor genes go silent. Hum Genet 111, 115-127.
Ge, X., and Wang, X. (2010). Role of Wnt canonical pathway in hematological malignancies. J Hematol Oncol 3, 33.
Goan, Y.G., Chang, H.C., Hsu, H.K., and Chou, Y.P. (2007). An audit of surgical outcomes of esophageal squamous cell carcinoma. Eur J Cardiothorac Surg 31, 536-544.
Gronbaek, K., Hother, C., and Jones, P.A. (2007). Epigenetic changes in cancer. APMIS 115, 1039-1059.
Gyobu, K., Yamashita, S., Matsuda, Y., Igaki, H., Niwa, T., Oka, D., Kushima, R., Osugi, H., Lee, S., Suehiro, S., and Ushijima, T. (2011). Identification and validation of DNA methylation markers to predict lymph node metastasis of esophageal squamous cell carcinomas. Ann Surg Oncol 18, 1185-1194.
Hamilton, J.P., Sato, F., Jin, Z., Greenwald, B.D., Ito, T., Mori, Y., Paun, B.C., Kan, T., Cheng, Y., Wang, S., Yang, J., Abraham, J.M., and Meltzer, S.J. (2006). Reprimo methylation is a potential biomarker of Barrett's-Associated esophageal neoplastic progression. Clin Cancer Res 12, 6637-6642.
Hayakawa, T., and Nakayama, J. (2011). Physiological roles of class I HDAC complex and histone demethylase. J Biomed Biotechnol 2011, 129383.
He, L.R., Liu, M.Z., Li, B.K., Rao, H.L., Liao, Y.J., Guan, X.Y., Zeng, Y.X., and Xie, D. (2009). Prognostic impact of H3K27me3 expression on locoregional progression after chemoradiotherapy in esophageal squamous cell carcinoma. BMC Cancer 9, 461.
He, Q., Chen, H.Y., Bai, E.Q., Luo, Y.X., Fu, R.J., He, Y.S., Jiang, J., and Wang, H.Q. (2010). Development of a multiplex MethyLight assay for the detection of multigene methylation in human colorectal cancer. Cancer Genet Cytogenet 202, 1-10.
Herman, J.G., and Baylin, S.B. (2003). Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349, 2042-2054.
Hu, N., Wang, C., Su, H., Li, W.J., Emmert-Buck, M.R., Li, G., Roth, M.J., Tang, Z.Z., Lu, N., Giffen, C., Albert, P.S., Taylor, P.R., and Goldstein, A.M. (2004). High frequency of CDKN2A alterations in esophageal squamous cell carcinoma from a high-risk Chinese population. Genes Chromosomes Cancer 39, 205-216.
I, H., Ko, E., Kim, Y., Cho, E.Y., Han, J., Park, J., Kim, K., Kim, D.H., and Shim, Y.M. (2010). Association of global levels of histone modifications with recurrence-free survival in stage IIB and III esophageal squamous cell carcinomas. Cancer Epidemiol Biomarkers Prev 19, 566-573.
Jauliac, S., Lopez-Rodriguez, C., Shaw, L.M., Brown, L.F., Rao, A., and Toker, A. (2002). The role of NFAT transcription factors in integrin-mediated carcinoma invasion. Nat Cell Biol 4, 540-544.
Ji, P., Diederichs, S., Wang, W., Boing, S., Metzger, R., Schneider, P.M., Tidow, N., Brandt, B., Buerger, H., Bulk, E., Thomas, M., Berdel, W.E., Serve, H., and Muller-Tidow, C. (2003). MALAT-1, a novel noncoding RNA, and thymosin beta4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene 22, 8031-8041.
Jia, Y., Yang, Y., Liu, S., Herman, J.G., Lu, F., and Guo, M. (2010). SOX17 antagonizes WNT/beta-catenin signaling pathway in hepatocellular carcinoma. Epigenetics 5, 743-749.
Jin, Z., Mori, Y., Yang, J., Sato, F., Ito, T., Cheng, Y., Paun, B., Hamilton, J.P., Kan, T., Olaru, A., David, S., Agarwal, R., Abraham, J.M., Beer, D., Montgomery, E., and Meltzer, S.J. (2007a). Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma. Oncogene 26, 6332-6340.
Jin, Z., Olaru, A., Yang, J., Sato, F., Cheng, Y., Kan, T., Mori, Y., Mantzur, C., Paun, B., Hamilton, J.P., Ito, T., Wang, S., David, S., Agarwal, R., Beer, D.G., Abraham, J.M., and Meltzer, S.J. (2007b). Hypermethylation of tachykinin-1 is a potential biomarker in human esophageal cancer. Clin Cancer Res 13, 6293-6300.
Jones, P.A., and Laird, P.W. (1999). Cancer epigenetics comes of age. Nat Genet 21, 163-167.
Jung, S., Yi, L., Jeong, D., Kim, J., An, S., Oh, T.J., Kim, C.H., Kim, C.J., Yang, Y., Kim, K.I., Lim, J.S., and Lee, M.S. (2011). The role of ADCYAP1, adenylate cyclase activating polypeptide 1, as a methylation biomarker for the early detection of cervical cancer. Oncol Rep 25, 245-252.
Kanehisa, M., and Goto, S. (2000). KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28, 27-30.
Kaneko, K., Kumekawa, Y., Makino, R., Nozawa, H., Hirayama, Y., Kogo, M., Konishi, K., Katagiri, A., Kubota, Y., Muramoto, T., Kushima, M., Ohmori, T., Oyama, T., Kagawa, N., Ohtsu, A., and Imawari, M. (2010). EGFR gene alterations as a prognostic biomarker in advanced esophageal squamous cell carcinoma. Front Biosci 15, 65-72.
Kato, K., Iida, S., Uetake, H., Takagi, Y., Yamashita, T., Inokuchi, M., Yamada, H., Kojima, K., and Sugihara, K. (2008). Methylated TMS1 and DAPK genes predict prognosis and response to chemotherapy in gastric cancer. Int J Cancer 122, 603-608.
Katoh, M. (2002). Molecular cloning and characterization of human SOX17. Int J Mol Med 9, 153-157.
Kim, M.S., Yamashita, K., Chae, Y.K., Tokumaru, Y., Chang, X., Zahurak, M., Osada, M., Park, H.L., Chuang, A., Califano, J.A., and Sidransky, D. (2007). A promoter methylation pattern in the N-methyl-D-aspartate receptor 2B gene predicts poor prognosis in esophageal squamous cell carcinoma. Clin Cancer Res 13, 6658-6665.
Kormish, J.D., Sinner, D., and Zorn, A.M. (2010). Interactions between SOX factors and Wnt/beta-catenin signaling in development and disease. Dev Dyn 239, 56-68.
Kostin, P.A., Zakharzhevskaia, N.B., Generozov, E.V., Govorun, V.M., Chernyshov, S.V., and Shchelygin Iu, A. (2010). [Hypermethylation of the CDH1, SEPT9, HLTF and ALX4 genes and their diagnostic significance in colorectal cancer]. Vopr Onkol 56, 162-168.
Kumekawa, Y., Kaneko, K., Ito, H., Kurahashi, T., Konishi, K., Katagiri, A., Yamamoto, T., Kuwahara, M., Kubota, Y., Muramoto, T., Mizutani, Y., and Imawari, M. (2006). Late toxicity in complete response cases after definitive chemoradiotherapy for esophageal squamous cell carcinoma. J Gastroenterol 41, 425-432.
Kuroki, T., Trapasso, F., Yendamuri, S., Matsuyama, A., Alder, H., Mori, M., and Croce, C.M. (2003a). Allele loss and promoter hypermethylation of VHL, RAR-beta, RASSF1A, and FHIT tumor suppressor genes on chromosome 3p in esophageal squamous cell carcinoma. Cancer Res 63, 3724-3728.
Kuroki, T., Trapasso, F., Yendamuri, S., Matsuyama, A., Alder, H., Mori, M., and Croce, C.M. (2003b). Promoter hypermethylation of RASSF1A in esophageal squamous cell carcinoma. Clin Cancer Res 9, 1441-1445.
Kuwano, H., Kato, H., Miyazaki, T., Fukuchi, M., Masuda, N., Nakajima, M., Fukai, Y., Sohda, M., Kimura, H., and Faried, A. (2005). Genetic alterations in esophageal cancer. Surg Today 35, 7-18.
Lahsnig, C., Mikula, M., Petz, M., Zulehner, G., Schneller, D., van Zijl, F., Huber, H., Csiszar, A., Beug, H., and Mikulits, W. (2009). ILEI requires oncogenic Ras for the epithelial to mesenchymal transition of hepatocytes and liver carcinoma progression. Oncogene 28, 638-650.
Lai, H.C., Lin, Y.W., Huang, T.H., Yan, P., Huang, R.L., Wang, H.C., Liu, J., Chan, M.W., Chu, T.Y., Sun, C.A., Chang, C.C., and Yu, M.H. (2008). Identification of novel DNA methylation markers in cervical cancer. Int J Cancer 123, 161-167.
Lai, M.C., Yang, Z., Zhou, L., Zhu, Q.Q., Xie, H.Y., Zhang, F., Wu, L.M., Chen, L.M., and Zheng, S.S. (2011). Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med Oncol.
Lee, E.J., Lee, B.B., Han, J., Cho, E.Y., Shim, Y.M., Park, J., and Kim, D.H. (2008). CpG island hypermethylation of E-cadherin (CDH1) and integrin alpha4 is associated with recurrence of early stage esophageal squamous cell carcinoma. Int J Cancer 123, 2073-2079.
Li, H., Myeroff, L., Smiraglia, D., Romero, M.F., Pretlow, T.P., Kasturi, L., Lutterbaugh, J., Rerko, R.M., Casey, G., Issa, J.P., Willis, J., Willson, J.K., Plass, C., and Markowitz, S.D. (2003). SLC5A8, a sodium transporter, is a tumor suppressor gene silenced by methylation in human colon aberrant crypt foci and cancers. Proc Natl Acad Sci U S A 100, 8412-8417.
Lin, J., Wang, Y.L., Qian, J., Yao, D.M., Zhu, Z.H., Qian, Z., and Xu, W.R. (2010). Aberrant methylation of DNA-damage-inducible transcript 3 promoter is a common event in patients with myelodysplastic syndrome. Leuk Res 34, 991-994.
Liu, Z., Zhang, L., Ding, F., Li, J., Guo, M., Li, W., Wang, Y., Yu, Z., Zhan, Q., and Wu, M. (2005). 5-Aza-2'-deoxycytidine induces retinoic acid receptor-beta(2) demethylation and growth inhibition in esophageal squamous carcinoma cells. Cancer Lett 230, 271-283.
Mandard, A.M., Hainaut, P., and Hollstein, M. (2000). Genetic steps in the development of squamous cell carcinoma of the esophagus. Mutat Res 462, 335-342.
Mandelker, D.L., Yamashita, K., Tokumaru, Y., Mimori, K., Howard, D.L., Tanaka, Y., Carvalho, A.L., Jiang, W.W., Park, H.L., Kim, M.S., Osada, M., Mori, M., and Sidransky, D. (2005). PGP9.5 promoter methylation is an independent prognostic factor for esophageal squamous cell carcinoma. Cancer Res 65, 4963-4968.
Matsui, T., Kanai-Azuma, M., Hara, K., Matoba, S., Hiramatsu, R., Kawakami, H., Kurohmaru, M., Koopman, P., and Kanai, Y. (2006). Redundant roles of Sox17 and Sox18 in postnatal angiogenesis in mice. J Cell Sci 119, 3513-3526.
Matsushima, K., Isomoto, H., Kohno, S., and Nakao, K. (2010). MicroRNAs and esophageal squamous cell carcinoma. Digestion 82, 138-144.
Meng, X.N., Jin, Y., Yu, Y., Bai, J., Liu, G.Y., Zhu, J., Zhao, Y.Z., Wang, Z., Chen, F., Lee, K.Y., and Fu, S.B. (2009). Characterisation of fibronectin-mediated FAK signalling pathways in lung cancer cell migration and invasion. Br J Cancer 101, 327-334.
Mummaneni, P., Walker, K.A., Bishop, P.L., and Turker, M.S. (1995). Epigenetic gene inactivation induced by a cis-acting methylation center. J Biol Chem 270, 788-792.
Murata, Y., Suzuki, S., Ohta, M., Mitsunaga, A., Hayashi, K., Yoshida, K., and Ide, H. (1996). Small ultrasonic probes for determination of the depth of superficial esophageal cancer. Gastrointest Endosc 44, 23-28.
Nagai, H., Tokumaru, S., Sayama, K., Shirakata, Y., Hanakawa, Y., Hirakawa, S., Dai, X., Tohyama, M., Yang, L., and Hashimoto, K. (2007). Suppressor of cytokine signaling 3 negative regulation of signal transducer and activator of transcription 3 in platelet-derived growth factor-induced fibroblast migration. J Dermatol 34, 523-530.
O'Donovan, P.J., and Livingston, D.M. (2010). BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. Carcinogenesis 31, 961-967.
Osugi, H., Takemura, M., Higashino, M., Takada, N., Lee, S., Ueno, M., Tanaka, Y., Fukuhara, K., Hashimoto, Y., Fujiwara, Y., and Kinoshita, H. (2003). Causes of death and pattern of recurrence after esophagectomy and extended lymphadenectomy for squamous cell carcinoma of the thoracic esophagus. Oncol Rep 10, 81-87.
Park, J.Y., Helm, J.F., Zheng, W., Ly, Q.P., Hodul, P.J., Centeno, B.A., and Malafa, M.P. (2008). Silencing of the candidate tumor suppressor gene solute carrier family 5 member 8 (SLC5A8) in human pancreatic cancer. Pancreas 36, e32-39.
Park, K.S., Wells, J.M., Zorn, A.M., Wert, S.E., and Whitsett, J.A. (2006). Sox17 influences the differentiation of respiratory epithelial cells. Dev Biol 294, 192-202.
Plass, C. (2002). Cancer epigenomics. Hum Mol Genet 11, 2479-2488.
Posner, M.C., Gooding, W.E., Landreneau, R.J., Rosenstein, M.M., Clarke, M.R., Peterson, M.S., and Lembersky, B.C. (1998). Preoperative chemoradiotherapy for carcinoma of the esophagus and gastroesophageal junction. Cancer J Sci Am 4, 237-246.
Roth, M.J., Abnet, C.C., Hu, N., Wang, Q.H., Wei, W.Q., Green, L., D'Alelio, M., Qiao, Y.L., Dawsey, S.M., Taylor, P.R., and Woodson, K. (2006). p16, MGMT, RARbeta2, CLDN3, CRBP and MT1G gene methylation in esophageal squamous cell carcinoma and its precursor lesions. Oncol Rep 15, 1591-1597.
Saitoh, Y., Obara, T., Einami, K., Nomura, M., Taruishi, M., Ayabe, T., Ashida, T., Shibata, Y., and Kohgo, Y. (1996). Efficacy of high-frequency ultrasound probes for the preoperative staging of invasion depth in flat and depressed colorectal tumors. Gastrointest Endosc 44, 34-39.
Shaffer, J.M., and Smithgall, T.E. (2009). Promoter methylation blocks FES protein-tyrosine kinase gene expression in colorectal cancer. Genes Chromosomes Cancer 48, 272-284.
Sharma, R.K., Rogojina, A.T., and Chalam, K.V. (2009). Multiplex immunoassay analysis of biomarkers in clinically accessible quantities of human aqueous humor. Mol Vis 15, 60-69.
Sigalas, I., Calvert, A.H., Anderson, J.J., Neal, D.E., and Lunec, J. (1996). Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nat Med 2, 912-917.
Sinner, D., Kordich, J.J., Spence, J.R., Opoka, R., Rankin, S., Lin, S.C., Jonatan, D., Zorn, A.M., and Wells, J.M. (2007). Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol Cell Biol 27, 7802-7815.
Sinner, D., Rankin, S., Lee, M., and Zorn, A.M. (2004). Sox17 and beta-catenin cooperate to regulate the transcription of endodermal genes. Development 131, 3069-3080.
Sohn, J., Natale, J., Chew, L.J., Belachew, S., Cheng, Y., Aguirre, A., Lytle, J., Nait-Oumesmar, B., Kerninon, C., Kanai-Azuma, M., Kanai, Y., and Gallo, V. (2006). Identification of Sox17 as a transcription factor that regulates oligodendrocyte development. J Neurosci 26, 9722-9735.
Su, H.Y., Lai, H.C., Lin, Y.W., Chou, Y.C., Liu, C.Y., and Yu, M.H. (2009). An epigenetic marker panel for screening and prognostic prediction of ovarian cancer. Int J Cancer 124, 387-393.
Taghavi, N., Biramijamal, F., Sotoudeh, M., Khademi, H., Malekzadeh, R., Moaven, O., Memar, B., A'Rabi, A., and Abbaszadegan, M.R. (2010). p16INK4a hypermethylation and p53, p16 and MDM2 protein expression in esophageal squamous cell carcinoma. BMC Cancer 10, 138.
Takeno, S., Noguchi, T., Fumoto, S., Kimura, Y., Shibata, T., and Kawahara, K. (2004). E-cadherin expression in patients with esophageal squamous cell carcinoma: promoter hypermethylation, Snail overexpression, and clinicopathologic implications. American journal of clinical pathology 122, 78-84.
Takeshita, H., Ichikawa, D., Komatsu, S., Tsujiura, M., Kosuga, T., Deguchi, K., Konishi, H., Morimura, R., Shiozaki, A., Fujiwara, H., Okamoto, K., and Otsuji, E. (2010). Prediction of CCND1 amplification using plasma DNA as a prognostic marker in oesophageal squamous cell carcinoma. Br J Cancer 102, 1378-1383.
Tanaka, K., Imoto, I., Inoue, J., Kozaki, K., Tsuda, H., Shimada, Y., Aiko, S., Yoshizumi, Y., Iwai, T., Kawano, T., and Inazawa, J. (2007). Frequent methylation-associated silencing of a candidate tumor-suppressor, CRABP1, in esophageal squamous-cell carcinoma. Oncogene 26, 6456-6468.
Thiagalingam, S., Foy, R.L., Cheng, K.H., Lee, H.J., Thiagalingam, A., and Ponte, J.F. (2002). Loss of heterozygosity as a predictor to map tumor suppressor genes in cancer: molecular basis of its occurrence. Curr Opin Oncol 14, 65-72.
Tibshirani, R., Hastie, T., Narasimhan, B., and Chu, G. (2002). Diagnosis of multiple cancer types by shrunken centroids of gene expression. Proc Natl Acad Sci U S A 99, 6567-6572.
Tzao, C., Sun, G.H., Tung, H.J., Hsu, H.S., Hsu, W.H., Wang, Y.C., Cheng, Y.L., and Lee, S.C. (2006). Reduced acetylated histone H4 is associated with promoter methylation of the fragile histidine triad gene in resected esophageal squamous cell carcinoma. Ann Thorac Surg 82, 396-401; discussion 401.
Tzao, C., Tung, H.J., Jin, J.S., Sun, G.H., Hsu, H.S., Chen, B.H., Yu, C.P., and Lee, S.C. (2009). Prognostic significance of global histone modifications in resected squamous cell carcinoma of the esophagus. Mod Pathol 22, 252-260.
Vaissiere, T., Hung, R.J., Zaridze, D., Moukeria, A., Cuenin, C., Fasolo, V., Ferro, G., Paliwal, A., Hainaut, P., Brennan, P., Tost, J., Boffetta, P., and Herceg, Z. (2009). Quantitative analysis of DNA methylation profiles in lung cancer identifies aberrant DNA methylation of specific genes and its association with gender and cancer risk factors. Cancer Res 69, 243-252.
Wang, J., Sasco, A.J., Fu, C., Xue, H., Guo, G., Hua, Z., Zhou, Q., Jiang, Q., and Xu, B. (2008). Aberrant DNA methylation of P16, MGMT, and hMLH1 genes in combination with MTHFR C677T genetic polymorphism in esophageal squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 17, 118-125.
Wang, Y., Fang, M.Z., Liao, J., Yang, G.Y., Nie, Y., Song, Y., So, C., Xu, X., Wang, L.D., and Yang, C.S. (2003). Hypermethylation-associated inactivation of retinoic acid receptor beta in human esophageal squamous cell carcinoma. Clin Cancer Res 9, 5257-5263.
Wang, Y.L., Qian, J., Lin, J., Yao, D.M., Qian, Z., Zhu, Z.H., and Li, J.Y. (2010). Methylation status of DDIT3 gene in chronic myeloid leukemia. J Exp Clin Cancer Res 29, 54.
Wegner, M. (1999). From head to toes: the multiple facets of Sox proteins. Nucleic Acids Res 27, 1409-1420.
Wu, C.Y., Lin, C.T., Wu, M.Z., and Wu, K.J. (2011). Induction of HSPA4 and HSPA14 by NBS1 overexpression contributes to NBS1-induced in vitro metastatic and transformation activity. J Biomed Sci 18, 1.
Xing, D., Tan, W., and Lin, D. (2003). Genetic polymorphisms and susceptibility to esophageal cancer among Chinese population (review). Oncol Rep 10, 1615-1623.
Xing, E.P., Nie, Y., Wang, L.D., Yang, G.Y., and Yang, C.S. (1999). Aberrant methylation of p16INK4a and deletion of p15INK4b are frequent events in human esophageal cancer in Linxian, China. Carcinogenesis 20, 77-84.
Yamasaki, M., Miyata, H., Fujiwara, Y., Takiguchi, S., Nakajima, K., Nishida, T., Yasuda, T., Matsuyama, J., Mori, M., and Doki, Y. (2010). p53 genotype predicts response to chemotherapy in patients with squamous cell carcinoma of the esophagus. Ann Surg Oncol 17, 634-642.
Yamashita, K., Kim, M.S., Park, H.L., Tokumaru, Y., Osada, M., Inoue, H., Mori, M., and Sidransky, D. (2008). HOP/OB1/NECC1 promoter DNA is frequently hypermethylated and involved in tumorigenic ability in esophageal squamous cell carcinoma. Mol Cancer Res 6, 31-41.
Yamashita, K., Upadhyay, S., Osada, M., Hoque, M.O., Xiao, Y., Mori, M., Sato, F., Meltzer, S.J., and Sidransky, D. (2002). Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. Cancer Cell 2, 485-495.
Yang, M.H., Chang, S.Y., Chiou, S.H., Liu, C.J., Chi, C.W., Chen, P.M., Teng, S.C., and Wu, K.J. (2007). Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer. Oncogene 26, 1459-1467.
Zhang, L., Lu, W., Miao, X., Xing, D., Tan, W., and Lin, D. (2003). Inactivation of DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relation to p53 mutations in esophageal squamous cell carcinoma. Carcinogenesis 24, 1039-1044.
Zhang, W., Glockner, S.C., Guo, M., Machida, E.O., Wang, D.H., Easwaran, H., Van Neste, L., Herman, J.G., Schuebel, K.E., Watkins, D.N., Ahuja, N., and Baylin, S.B. (2008). Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. Cancer Res 68, 2764-2772.
Zorn, A.M., Barish, G.D., Williams, B.O., Lavender, P., Klymkowsky, M.W., and Varmus, H.E. (1999). Regulation of Wnt signaling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin. Mol Cell 4, 487-498.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2014-08-09起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2014-08-09起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw