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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 華國泰(Kuo-Tai Hua) | |
| dc.contributor.author | Meng-Ting Ko | en |
| dc.contributor.author | 柯孟廷 | zh_TW |
| dc.date.accessioned | 2021-06-17T07:37:44Z | - |
| dc.date.available | 2024-08-26 | |
| dc.date.copyright | 2019-08-26 | |
| dc.date.issued | 2019 | |
| dc.date.submitted | 2019-03-22 | |
| dc.identifier.citation | 1. 衛生福利部國民健康署（2006）。 95年癌症登記報告。臺北：行政院。
2. 衛生福利部國民健康署（2016）。 105年癌症登記報告。臺北：行政院。 3. Abal, M., Planaguma, J., Gil-Moreno, A., Monge, M., Gonzalez, M., Baro, T., Garcia, A., Castellvi, J., Ramon, Y., Cajal, S., Xercavins, J., Alameda, F., & Reventos, J. (2006). Molecular pathology of endometrial carcinoma: transcriptional signature in endometrioid tumors. Histol Histopathol, 21(2), 197-204. 4. Asipu, A., Hayward, B.E., O'Reilly, J., & Bonthron, D.T. (2003). Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria. Diabetes, 52(9), 2426-2432. 5. Bais, R., James, H.M., Rofe, A.M., & Conyers, R.A. (1985). The purification and properties of human liver ketohexokinase. A role for ketohexokinase and fructose-bisphosphate aldolase in the metabolic production of oxalate from xylitol. Biochem J, 230(1), 53-60. 6. Biswas, D.K., Shi, Q., Baily, S., Strickland, I., Ghosh, S., Pardee, A.B., & Iglehart, J.D. (2004). NF-kappa B activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci U S A, 101(27), 10137-10142. 7. Bonthron, D.T., Brady, N., Donaldson, I.A., & Steinmann, B. (1994). Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet, 3(9), 1627-1631. 8. Byun, J.M., Jeong, D.H., Kim, Y.N., Cho, E.B., Cha, J.E., Sung, M.S., Lee, K.B., & Kim, K.T. (2015). Endometrial cancer arising from atypical complex hyperplasia: The significance in an endometrial biopsy and a diagnostic challenge. Obstet Gynecol Sci, 58(6), 468-474. 9. Carpenter, R.L., & Lo, H.W. (2012). Hedgehog pathway and GLI1 isoforms in human cancer. Discov Med, 13(69), 105-113. 10. Carvalho, M.J., Laranjo, M., Abrantes, A.M., Torgal, I., Botelho, M.F., & Oliveira, C.F. (2015). Clinical translation for endometrial cancer stem cells hypothesis. Cancer Metastasis Rev. 34(3), 401-416. 11. Chan, R.W., Schwab, K.E., & Gargett, C.E. (2004). Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod, 70(6), 1738-1750. 12. Chan, R.W., & Gargett, C.E. (2006). Identification of label-retaining cells in mouse endometrium. Stem Cells, 24(6), 1529-1538. 13. Chen, J.C., & Roan, N.R. (2015). Isolation and Culture of Human Endometrial Epithelial Cells and Stromal Fibroblasts. Bio Protoc, 5(20), e1623. 14. Clark, D.W., & Palle, K. (2016). Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets. Ann Transl Med, 4(24), 518. 15. Cochrane, C.R., Szczepny, A., Watkins, D.N., & Cain, J.E. (2015). Hedgehog Signaling in the Maintenance of Cancer Stem Cells. Cancers (Basel), 7(3), 1554-1585. 16. Colombo, N., Preti, E., Landoni, F., Carinelli, S., Colombo, A., Marini, C., & Sessa, C. (2013). Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 24(Suppl 6), vi33-38. 17. Dellinger, T.H., Planutis, K., Tewari, K.S., & Holcombe, R.F. (2012). Role of canonical Wnt signaling in endometrial carcinogenesis. Expert Rev Anticancer Ther, 12(1), 51-62. 18. Denschlag, D., Ulrich, U., & Emons, G. (2010). The diagnosis and treatment of endometrial cancer: progress and controversies. Dtsch Arztebl Int, 108(34-35), 571-577. 19. De Sousa E Melo, F., & Vermeulen, L. (2016). Wnt Signaling in Cancer Stem Cell Biology. Cancers (Basel), 8(7), pii, E60. 20. Diggle, C.P., Shires, M., Leitch, D., Brooke, D., Carr, I.M., Markham, A.F., Hayward, B.E., Asipu, A., & Bonthron, D.T. (2009). Ketohexokinase: Expression and Localization of the Principal Fructose-metabolizing Enzyme. J Histochem Cytochem, 57(8), 763-774. 21. Ding, D.C., Liu, H.W., Chang, Y.H., & Chu, T.Y. (2017). Expression of CD133 in endometrial cancer cells and its implications. J Cancer, 8(11), 2142-2153. 22. Doke, T., Ishimoto, T., Hayasaki, T., Ikeda, S., Hasebe, M., Hirayama, A., Soga, T., Kato, N., Kosugi, T., Tsuboi, N., Lanaspa, M.A., Johnson, R.J., Kadomatsu, K., & Maruyama, S. (2018). Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice. Metabolism, 85, 161-170. 23. Elbasateeny, S.S., Salem, A.A., Abdelsalam, W.A., & Salem, R.A. (2016). Immunohistochemical expression of cancer stem cell related markers CD44 and CD133 in endometrial cancer. Pathol Res Pract, 212(1), 10-16. 24. Feng, Y.Z., Shiozawa, T., Miyamoto, T., Kashima, H., Kurai, M., Suzuki, A., Ying-Song, J., & Konishi, I. (2007). Overexpression of hedgehog signaling molecules and its involvement in the proliferation of endometrial carcinoma cells. Clin Cancer Res, 13(5), 1389-1398. 25. Fukuchi, T., Sakamoto, M., Tsuda, H., Maruyama, K., Nozawa, S., & Hirohashi, S. (1998). Beta-catenin mutation in carcinoma of the uterine endometrium. Cancer Res, 58(16), 3526-3528. 26. Gao, W., Li, N., Li, Z., Xu, J., & Su, C. (2018). Ketohexokinase is involved in fructose utilization and promotes tumor progression in glioma. Biochem Biophys Res Commun, 503(3), 1298-1306. 27. Gargett, C.E., & Masuda, H. (2010). Adult stem cells in the endometrium. Mol Hum Reprod, 16(11), 818-834. 28. Gordon, M.D., & Ireland, K. (2008). Pathology of Endometrial Carcinoma. Glob. libr. women's med, 1756-2228. 29. Hubbard, S.A., Friel, A.M., Kumar, B., Zhang, L., Rueda, B.R., & Gargett, C.E. (2009). Evidence for cancer stem cells in human endometrial carcinoma. Cancer Res, 69(21), 8241-8248. 30. Huijgens, A.N., & Mertens, H.J. (2013). Factors predicting recurrent endometrial cancer. Facts Views Vis Obgyn, 5(3), 179-186. 31. Hwa, J.S., Kim, H.J., Goo, B.M., Park, H.J., Kim, C.W., Chung, K.H., Park, H.C., Chang, S.H., Kim, Y.W., Kim, D.R., Cho, G.J., Choi, W.S., & Kang, K.R. (2006). The expression of ketohexokinase is diminished in human clear cell type of renal cell carcinoma. Proteomics, 6(3), 1077-1084. 32. Ishimoto, T., Lanaspa, M.A., Le, M.T., Garcia, G.E., Diggle, C.P., Maclean, P.S., Jackman M.R., Asipu, A., Roncal-Jimenez, C.A., Kosugi, T., Rivard, C.J., Maruyama, S, Rodriguez-Iturbe B., Sánchez-Lozada, L.G., Bonthron, D.T., Sautin, Y.Y., & Johnson, R.J. (2012). Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. Proc Natl Acad Sci U S A, 109(11), 4320-4325. 33. Kong, F.F., Li, D., Yang, H., Ma, J., Pan, X., Liu, H.X., Huo, J.N., & Ma, X.X. (2017). Preliminary identification of endometrial cancer stem cells in vitro and in vivo. Biochem Biophys Res Commun, 490(2), 506-513. 34. Kurnit, K.C., Kim, G.N., Fellman, B.M., Urbauer, D.L., Mills, G.B., Zhang, W., & Broaddus, R.R. (2017). CTNNB1 (beta-catenin) mutation identifies low grade, early stage endometrial cancer patients at increased risk of recurrence. Mod Pathol, 30(7), 1032-1041. 35. Kyo, S., & Kato, K. (2015). Endometrial Cancer Stem Cell as a Potential Therapeutic Target. Semin Reprod Med, 33(5), 341-349. 36. Lanaspa, M.A., Andres-Hernando, A., Orlicky, D.J., Cicerchi, C., Jang, C., Li, N., Milagres, T., Kuwabara, M., Wempe, M.F., Rabinowitz, J.D., Johnson, R.J., & Tolan, D.R. (2018). Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. J Clin Invest, 128(6), 2226-2238. 37. Li, X., Qian, X., Peng, L.X., Jiang, Y., Hawke, D.H., Zheng, Y., Xia, Y., Lee, J.H., Cote, G., Wang, H., Wang, L., Qian, C.N., & Lu, Z. (2016). A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation. Nat Cell Biol, 18(5), 561-571. 38. Liao, X., Siu, M.K., Au, C.W., Chan, Q.K., Chan, H.Y., Wong, E.S., Ip, P.P., Ngan, H.Y., & Cheung, A.N. (2009). Aberrant activation of hedgehog signaling pathway contributes to endometrial carcinogenesis through beta-catenin. Mod Pathol, 22(6), 839-847. 39. Kiewisz, J., Wasniewski, T., & Kmiec, Z. (2015). Participation of WNT and β-Catenin in Physiological and Pathological Endometrial Changes: Association with Angiogenesis. Biomed Res Int, 2015, 854056. 40. Markowska, A., Pawałowska, M., Lubin, J., & Markowska, J. (2014). Signalling pathways in endometrial cancer. Contemp Oncol (Pozn), 18(3), 143-148. 41. Mizumoto, Y., Kyo, S., Kiyono, T., Takakura, M., Nakamura, M., Maida, Y., Mori, N., Bono, Y., Sakurai, H., & Inoue, M. (2011). Activation of NF-kappaB is a novel target of KRAS-induced endometrial carcinogenesis. Clin Cancer Res, 17(6), 1341-1350. 42. Morice, P., Leary, A., Creutzberg, C., Abu-Rustum, N., & Darai, E. (2016). Endometrial cancer. Lancet, 387(10023), 1094-1108. 43. Pallares, J., Martínez-Guitarte, J.L., Dolcet, X., Llobet, D., Rue, M., Palacios, J., Prat, J., & Matias-Guiu, X. (2004). Abnormalities in the NF-kappaB family and related proteins in endometrial carcinoma. J Pathol, 204(5), 569-577. 44. Patel, C., Douard, V., Yu, S., Tharabenjasin, P., Gao, N., & Ferraris, R.P. (2015). Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK. Am J Physiol Regul Integr Comp Physiol, 309(5), R499-509. 45. Pityński, K., Banas, T., Pietrus, M., Milian-Ciesielska, K., Ludwin, A., & Okon, K. (2015). SOX-2, but not Oct4, is highly expressed in early-stage endometrial adenocarcinoma and is related to tumour grading. Int J Clin Exp Pathol, 8(7), 8189–8198. 46. O'Hara, A.J., & Bell, D.W. (2012). The genomics and genetics of endometrial cancer. Adv Genomics Genet, 2012(2), 33-47. 47. Rahadiani, N., Ikeda, J., Mamat, S., Matsuzaki, S., Ueda, Y., Umehara, R., Tian, T., Wang, Y., Enomoto, T., Kimura, T., Aozasa, K., & Morii, E. (2011). Expression of aldehyde dehydrogenase 1 (ALDH1) in EAC and its clinical implications. Cancer Sci, 102(4), 903-908. 48. Rauch, J., Moran-Jones, K., Albrecht, V., Schwarzl, T., Hunter, K., Gires, O., & Kolch, W. (2011). c-Myc regulates RNA splicing of the A-Raf kinase and its activation of the ERK pathway. Cancer Res, 71(13), 4664-4674. 49. Rinkenbaugh, A.L., & Baldwin, A.S. (2016). The NF-κB Pathway and Cancer Stem Cells. Cells. 5(2), pii, E16. 50. Rutella, S., Bonanno, G., Procoli, A., Mariotti, A., Corallo, M., Prisco, M.G., Eramo, A., Napoletano, C., Gallo, D., Perillo, A., Nuti, M., Pierelli, L., Testa, U., Scambia, G., & Ferrandina, G. (2009). Cells with characteristics of cancer stem/progenitor cells express the CD133 antigen in human endometrial tumors. Clin Cancer Res, 15(13), 4299-4311. 51. Scholten, A.N., Creutzberg, C.L., van den Broek, L.J., Noordijk, E.M., & Smit, V.T. (2003). Nuclear beta-catenin is a molecular feature of type I endometrial carcinoma. J Pathol, 201(3), 460-465. 52. Tomita, H., Tanaka, K., Tanaka, T., & Hara, A. (2016). Aldehyde dehydrogenase 1A1 in stem cells and cancer. Oncotarget, 7(10), 11018-11032. 53. Trinh, C.H., Asipu, A., Bonthron, D.T., & Phillips, S.E. (2009). Structures of alternatively spliced isoforms of human ketohexokinase. Acta Crystallogr D Biol Crystallogr, 65(3), 201-211. 54. Van Schaftingen, E. (1989). A protein from rat liver confers to glucokinase the property of being antagonistically regulated by fructose 6-phosphate and fructose 1-phosphate. Eur J Biochem, 179(1), 179-184. 55. Wang, Y., van der Zee, M., Fodde, R., & Blok, L.J. (2010). Wnt/Β-catenin and sex hormone signaling in endometrial homeostasis and cancer. Oncotarget, 1(7), 674-684. 56. Yeramian, A., García, V., Bergadà, L., Domingo, M., Santacana, M., Valls, J., Martinez-Alonso, M., Carceller, J.A., Cussac, A.L., Dolcet, X., & Matias-Guiu, X. (2016). Bioluminescence Imaging to Monitor the Effects of the Hsp90 Inhibitor NVP-AUY922 on NF-κB Pathway in Endometrial Cancer. Mol Imaging Biol, 18(4), 545-556. 57. Yu, Z., Pestell, T.G., Lisanti, M.P., & Pestell, R.G. (2012). Cancer Stem Cells. Int J Biochem Cell Biol, 44(12), 2144–2151. 58. Zhang, J., Song, H., Lu, Y., Chen, H., Jiang, S., & Li, L. (2016). Effects of estradiol on VEGF and bFGF by Akt in endometrial cancer cells are mediated through the NF-κB pathway. Oncol Rep, 36(2), 705-714. 59. Zhou, Q., Singh, S.R., Tina, S.S.D., Wena, J., Yiying, Z., & Mariella, M.S. (2018). The Pathways in Endometrial Carcinogenesis and an Overview of its Histology, Grade and Stage. Ann Clin Lab Res, 6(1), 231. 60. Zimonjic, D.B., & Popescu, N.C. (2012). Role of DLC1 tumor suppressor gene and MYC oncogene in pathogenesis of human hepatocellular carcinoma: potential prospects for combined targeted therapeutics (review). Int J Oncol, 41(2), 393-406. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73487 | - |
| dc.description.abstract | 己酮糖磷酸酶（Ketohexokinase, KHK）在過去的研究中被發現具有果糖代謝的功能，能將果糖磷酸化使其進入三羧酸循環代謝。過去研究發現KHK-A能藉由刺激核苷酸合成促進癌細胞生長引起我們的興趣。分析KHK在各種不同的癌症中臨床上的重要性後，選擇子宮內膜癌做為我們的癌症模式。子宮內膜癌逐年升高的發生率近年來已成為不可忽視的問題，其中超過八成的個案為子宮內膜腺癌，因此我們希望探討KHK在子宮內膜腺癌的角色，並進一步評估未來是否可能作為子宮內膜腺癌的生物標記。首先我們分析了The Cancer Genome Atlas (TCGA) 資料庫，發現KHK表現量高的病人預後較差，並與其他預後因子包括了臨床階段與組織分級顯著相關，且這樣的現象只出現在子宮內膜腺癌的病人中，因此KHK更能作為獨立的預後因子。接著我們分析臨床病人檢體後發現KHK只在癌細胞中高度表現，且進一步將正常子宮內膜的表皮細胞與癌細胞做比較後印證了此項結果，還發現癌細胞中高度表現的KHK以KHK-A的形式佔多數。細胞實驗中，我們透過抑制KHK以及過度表現KHK-A或KHK-C的方式觀察其對於癌細胞各種功能的影響，發現KHK能促進癌細胞的生長，且對於癌細胞長期的生長較為明顯，也能驅使與腫瘤新生相關的非貼附性生長，甚至能更進一步促使癌幹細胞生成。動物實驗中，同樣可以發現高度表現KHK的組別，腫瘤也長得越大。最後，我們針對三個先前已知與癌幹細胞以及腫瘤新生相關的重要轉錄因子分別為Hedgehog路徑中的GLI1、Wnt路徑中的β-catenin和NF-κB路徑中的NF-κB/p65做分析，發現KHK-A以及KHK-C皆會入核，且會促使GLI1、β-catenin和NF-κB/p65細胞核表現量以及活性微幅增加。總結來說，KHK可能會透過調控GLI1、β-catenin和NF-κB/p65促進子宮內膜腺癌生長，腫瘤新生以及癌幹細胞生成。 | zh_TW |
| dc.description.abstract | Ketohexokinase (KHK) is a rate-limiting enzyme of fructose metabolism. It can phosphorylate the fructose to generate fructose-1-phosphate which is the precursor of tricarboxylic acid cycle. However, it interested us that KHK-A isoform was discovered to induce cancer cell proliferation through nucleotide synthesis. As a result, we analyzed the correlation between KHK expression and patient survival in sixteen kinds of cancer type in clinical database and chose the endometrial cancer (EC) as our cancer model. The rising incidence of EC is too serious to ignore this problem. Further, endometrioid adenocarcinoma (EAC) accounts for over 80% of new cases of EC. Hence, we wanted to investigate the roles of KHK in EAC. Furthermore, we evaluated whether KHK could become a novel biomarker of EAC in the future. First, we found overexpression of KHK was correlated to poor survival, late clinical stage, and high histologic grade of EC patients in The Cancer Genome Atlas (TCGA) database. In addition, KHK can be regarded as the independent unfavorable-prognostic factor of EAC. After that, we collected the normal, hyperplastic, cancerous endometrial tissues from patients and found KHK overexpressed in cancerous tissue. These results were supported by the comparison of endometrial epithelial cells (eECs) and EAC cells. Besides that, there are almost all of increment of KHK was KHK-A isoform. We observed KHK affected the functions of cancer cells through knockdown of KHK and overexpression of KHK-A or KHK-C. In vitro, we found KHK induced the proliferation of EAC, especially long term proliferation. On the other hand, KHK promoted anchorage-independent growth and cancer stemness. In vivo, the average tumor size was bigger in the KHK-overexpressed groups compared with the control. Finally, we chose the cancer-stemness-related transcription factors GLI1, β-catenin, and NF-κB/p65 as potential target genes of KHK. We found the KHK can boost the GLI1, β-catenin, and NF-κB/p65 expression and activity slightly. In conclusion, KHK can induce the proliferation, tumorigenesis, and cancer stemness of EAC through GLI1, β-catenin, and NF-κB/p65 activation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T07:37:44Z (GMT). No. of bitstreams: 1 ntu-108-R05447007-1.pdf: 9855946 bytes, checksum: 1f5095c08c4b64ce1a7905b878ff4303 (MD5) Previous issue date: 2019 | en |
| dc.description.tableofcontents | 口試委員會審定書 I
誌謝 II Abbreviations III 中文摘要 IV Abstract V Contents VII List of Figures IX List of Tables X Chapter 1: Introductions 1 1.1 Ketohexokinase 2 1.2 Endometrial cancer 5 1.3 Research motivation 7 Chapter 2: Materials and Methods 9 Chapter 3: Results 26 3.1 KHK expression was unfavorable-prognostic factor of EC 27 3.2 KHK expression was positively correlated to EAC progression 27 3.3 KHK expression was positively correlated to endometrial carcinogenesis 29 3.4 Knockdown of KHK expression suppressed the proliferation, tumorigenesis and cancer stemness of EAC in vitro 30 3.5 Overexpression of KHK promoted the proliferation, tumorigenesis and cancer stemness of EAC in vitro. 32 3.6 Overexpression of KHK promoted EAC progression in vivo 33 3.7 KHK probably regulated nuclear translocation and activity of GLI1, β-catenin, and NF-κB/p65 in EAC 34 Chapter 4: Discussions 36 Figures and Figure Legends 44 Tables 76 References 81 | |
| dc.language.iso | en | |
| dc.subject | 子宮內膜癌 | zh_TW |
| dc.subject | 己酮糖磷酸激? | zh_TW |
| dc.subject | 腫瘤新生 | zh_TW |
| dc.subject | 癌幹細胞 | zh_TW |
| dc.subject | 入核作用 | zh_TW |
| dc.subject | Nuclear translocation | en |
| dc.subject | Ketohexokinase | en |
| dc.subject | Tumorigenesis | en |
| dc.subject | Endometrial cancer | en |
| dc.subject | Cancer stem cells | en |
| dc.title | 探討己酮糖磷酸激酶在子宮內膜腺癌惡性進程之角色 | zh_TW |
| dc.title | Evaluation of the Roles of Ketohexokinase
in Endometrioid Adenocarcinoma Progression | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 107-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 魏凌鴻(Ling-Hong Wei),翁孟仕(Meng-Shih Weng),簡銘賢(Ming-Hsien Chien) | |
| dc.subject.keyword | 子宮內膜癌,己酮糖磷酸激?,腫瘤新生,癌幹細胞,入核作用, | zh_TW |
| dc.subject.keyword | Endometrial cancer,Ketohexokinase,Tumorigenesis,Cancer stem cells,Nuclear translocation, | en |
| dc.relation.page | 88 | |
| dc.identifier.doi | 10.6342/NTU201900659 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2019-03-24 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 毒理學研究所 | zh_TW |
| 顯示於系所單位： | 毒理學研究所 | |
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