請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73860
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 黃敏銓(Min-Chuan Huang) | |
dc.contributor.author | Ting-Chun Kuo | en |
dc.contributor.author | 郭庭均 | zh_TW |
dc.date.accessioned | 2021-06-17T08:12:07Z | - |
dc.date.available | 2021-02-23 | |
dc.date.copyright | 2021-02-23 | |
dc.date.issued | 2021 | |
dc.date.submitted | 2021-01-31 | |
dc.identifier.citation | 1. Klein AP, Brune KA, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 2004; 64: 2634-2638. 2. Tanaka S. Molecular Pathogenesis and Targeted Therapy of Pancreatic Cancer. Ann Surg Oncol 2016; 23 Suppl 2: S197-205. 3. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med (Review) 2014; 371: 1039-1049. 4. Administration HP. Health Promotion Administration Annual Report. Ministry of Health and Welfare 2019. 5. Edge SB BD, Compton CC. Exocrine and endocrine pancreas, in AJCC Cancer Staging Manual2010: 241-249. 6. Davies K, Conlon KC. Neuroendocrine tumors of the pancreas. Curr Gastroenterol Rep 2009; 11: 119-127. 7. Kulke MH, Siu LL, Tepper JE, Fisher G, Jaffe D, Haller DG et al. Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. J Clin Oncol 2011; 29: 934-943. 8. Varadhachary GR, Tamm EP, Abbruzzese JL, Xiong HQ, Crane CH, Wang H et al. Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg Oncol 2006; 13: 1035-1046. 9. Wu YM, Liu CH, Huang MJ, Lai HS, Lee PH, Hu RH et al. C1GALT1 enhances proliferation of hepatocellular carcinoma cells via modulating MET glycosylation and dimerization. Cancer Res 2013; 73: 5580-5590. 10. Conroy T, Hammel P, Hebbar M, Ben Abdelghani M, Wei AC, Raoul JL et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med 2018; 379: 2395-2406. 11. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369: 1691-1703. 12. Ueno H, Kosuge T, Matsuyama Y, Yamamoto J, Nakao A, Egawa S et al. A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer. Br J Cancer 2009; 101: 908-915. 13. Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res 2012; 18: 4266-4276. 14. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011; 331: 1612-1616. 15. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 2014; 25: 719-734. 16. Molina V, Visa L, Conill C, Navarro S, Escudero JM, Auge JM et al. CA 19-9 in pancreatic cancer: retrospective evaluation of patients with suspicion of pancreatic cancer. Tumour Biol 2012; 33: 799-807. 17. Locker GY. ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. Journal of Clinical Oncology 2006; 24: 5313-5327. 18. Kang R, Tang D, Lotze MT, Zeh HJ, 3rd. RAGE regulates autophagy and apoptosis following oxidative injury. Autophagy 2011; 7: 442-444. 19. Julien S, P.A. Videira, and P. Delannoy. Sialyl-tn in cancer: (how) did we miss the target? Biomolecules 2012; 2: 435-466. 20. Aryal RP, T.Z. Ju, and R.D. Cummings. Identification of a Novel Protein Binding Motif within the T-synthase for the Molecular Chaperone Cosmc. Journal of Biological Chemistry 2014; 289: 11630-11641. 21. Ten Hagen KG, Fritz TA, Tabak LA. All in the family: the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases. Glycobiology 2003; 13: 1R-16R. 22. Bennett EP, Mandel U, Clausen H, Gerken TA, Fritz TA, Tabak LA. Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family. Glycobiology 2012; 22: 736-756. 23. Azmi A. Proteomics in Pancreatic Cancer Translational Research, in Molecular Diagnostics and Treatment of Pancreatic Cancer. Systems and Network Biology Approaches 2014: 197-219. 24. Chou CH, Huang MJ, Chen CH, Shyu MK, Huang J, Hung JS et al. Up-regulation of C1GALT1 promotes breast cancer cell growth through MUC1-C signaling pathway. Oncotarget 2015; 6: 6123-6135. 25. Lee PC, Chen ST, Kuo TC, Lin TC, Lin MC, Huang J et al. C1GALT1 is associated with poor survival and promotes soluble Ephrin A1-mediated cell migration through activation of EPHA2 in gastric cancer. Oncogene 2020; 39: 2724-2740. 26. Hung JS, Huang J, Lin YC, Huang MJ, Lee PH, Lai HS et al. C1GALT1 overexpression promotes the invasive behavior of colon cancer cells through modifying O-glycosylation of FGFR2. Oncotarget 2014; 5: 2096-2106. 27. Zhang C, Deng X, Qiu L, Peng F, Geng S, Shen L et al. Knockdown of C1GalT1 inhibits radioresistance of human esophageal cancer cells through modifying beta1-integrin glycosylation. J Cancer 2018; 9: 2666-2677. 28. Lin MC, Chien PH, Wu HY, Chen ST, Juan HF, Lou PJ et al. C1GALT1 predicts poor prognosis and is a potential therapeutic target in head and neck cancer. Oncogene 2018; 37: 5780-5793. 29. Bennett EP, Hassan H, Mandel U, Hollingsworth MA, Akisawa N, Ikematsu Y et al. Cloning and characterization of a close homologue of human UDP-N-acetyl-alpha-D-galactosamine:Polypeptide N-acetylgalactosaminyltransferase-T3, designated GalNAc-T6. Evidence for genetic but not functional redundancy. J Biol Chem 1999; 274: 25362-25370. 30. Radhakrishnan P, Dabelsteen S, Madsen FB, Francavilla C, Kopp KL, Steentoft C et al. Immature truncated O-glycophenotype of cancer directly induces oncogenic features. Proc Natl Acad Sci U S A 2014; 111: E4066-4075. 31. Cunningham D, Chau I, Stocken DD, Valle JW, Smith D, Steward W et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 2009; 27: 5513-5518. 32. Cao LP, Song JL, Yi XP, Li YX. Double inhibition of NF-kappaB and XIAP via RNAi enhances the sensitivity of pancreatic cancer cells to gemcitabine. Oncol Rep 2013; 29: 1659-1665. 33. Schmitt CAaSWL. Apoptosis is critical for drug response in vivo. Drug Resist Updat 2001; 4: 132-134. 34. Park SH, Sung JH, Kim EJ, Chung N. Berberine induces apoptosis via ROS generation in PANC-1 and MIA-PaCa2 pancreatic cell lines. Braz J Med Biol Res 2015; 48: 111-119. 35. Garrido-Laguna I, Hidalgo M. Pancreatic cancer: from state-of-the-art treatments to promising novel therapies. Nat Rev Clin Oncol 2015; 12: 319-334. 36. Franco-Barraza J, Francescone R, Luong T, Shah N, Madhani R, Cukierman G et al. Matrix-regulated integrin alphavbeta5 maintains alpha5beta1-dependent desmoplastic traits prognostic of neoplastic recurrence. Elife 2017; 6. 37. Liu CH, Hu RH, Huang MJ, Lai IR, Chen CH, Lai HS et al. C1GALT1 promotes invasive phenotypes of hepatocellular carcinoma cells by modulating integrin beta1 glycosylation and activity. PLoS One 2014; 9: e94995. 38. Saitoh M. Involvement of partial EMT in cancer progression. J Biochem 2018; 164: 257-264. 39. Guan JL. Role of focal adhesion kinase in integrin signaling. Int J Biochem Cell Biol 1997; 29: 1085-1096. 40. Mitra SK, Mikolon D, Molina JE, Hsia DA, Hanson DA, Chi A et al. Intrinsic FAK activity and Y925 phosphorylation facilitate an angiogenic switch in tumors. Oncogene 2006; 25: 5969-5984. 41. Guan JL. Integrin signaling through FAK in the regulation of mammary stem cells and breast cancer. IUBMB Life 2010; 62: 268-276. 42. Chen CH, Shyu MK, Wang SW, Chou CH, Huang MJ, Lin TC et al. MUC20 promotes aggressive phenotypes of epithelial ovarian cancer cells via activation of the integrin beta1 pathway. Gynecol Oncol 2016; 140: 131-137. 43. Adorno-Cruz V, Liu H. Regulation and functions of integrin alpha2 in cell adhesion and disease. Genes Dis 2019; 6: 16-24. 44. Hatley RJD, Macdonald SJF, Slack RJ, Le J, Ludbrook SB, Lukey PT. An alphav-RGD Integrin Inhibitor Toolbox: Drug Discovery Insight, Challenges and Opportunities. Angew Chem Int Ed Engl 2018; 57: 3298-3321. 45. Weis SM, Cheresh DA. alphaV integrins in angiogenesis and cancer. Cold Spring Harb Perspect Med 2011; 1: a006478. 46. Chen ST, Kuo TC, Liao YY, Lin MC, Tien YW, Huang MC. Silencing of MUC20 suppresses the malignant character of pancreatic ductal adenocarcinoma cells through inhibition of the HGF/MET pathway. Oncogene 2018; 37: 6041-6053. 47. Chugh S, Barkeer S, Rachagani S, Nimmakayala RK, Perumal N, Pothuraju R et al. Disruption of C1galt1 Gene Promotes Development and Metastasis of Pancreatic Adenocarcinomas in Mice. Gastroenterology 2018; 155: 1608-1624. 48. El-Brolosy MA, Stainier DYR. Genetic compensation: A phenomenon in search of mechanisms. PLoS Genet 2017; 13: e1006780. 49. Duggan MA, Anderson WF, Altekruse S, Penberthy L, Sherman ME. The Surveillance, Epidemiology, and End Results (SEER) Program and Pathology: Toward Strengthening the Critical Relationship. Am J Surg Pathol 2016; 40: e94-e102. 50. Landman A, Feetham L, Stuckey D. Working together to reduce the burden of pancreatic cancer. The Lancet Oncology 2020; 21: 334-335. 51. Jutric Z, Melstrom LG. New Treatment Options and Management Considerations in Borderline Resectable Pancreatic Cancer. Oncology (Williston Park) 2017; 31: 443-452. 52. Chiorean EG, Coveler AL. Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies. Drug Des Devel Ther 2015; 9: 3529-3545. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/73860 | - |
dc.description.abstract | 胰臟癌致死率極高,在其中有高達百分之九十五為胰管腺癌,死亡率居國人十大癌症死因之七、全球之第四、甚至被預測在二零三零年將會成為美國第二癌症死因,其增加率卻高居第一且近三十年來並無顯著進展;目前最有效治療方式仍為根除性手術,卻只有百分之十五至二十的病人屬於可切除之胰臟癌,且即便完整廓清其預後仍不盡理想,輔助性化學放射治療或標靶治療效果亦不彰,胰臟癌之致病機轉仍深陷迷霧。 醣化是蛋白質最為常見且最複雜的轉譯後修飾作用,大部分的腫瘤都被發現有異常的醣類表現,例如Tn抗原和T抗原。蛋白醣化作用主要分為氧型蛋白醣化作用及氮型蛋白醣化作用,最普遍的氧型蛋白醣化作用為黏液型,N-乙醯基半乳糖胺基轉移酵素負責開啟黏液型醣化的第一步驟,在絲胺酸或蘇胺酸加上N-乙醯半乳糖胺,形成Tn抗原。蛋白醣化酵素(core 1 β1,3-galactosyltransferase, C1GALT1)進一步加上半乳糖,形成T抗原。過去研究指出Tn抗原、T抗原以及蛋白醣化酵素C1GALT1的過度表現與乳癌、胃癌、大腸癌、肝癌、頭頸癌、卵巢癌、攝護腺癌等之臨床病生理、腫瘤惡性表現度、及病患預後存活有關,然而在胰臟癌中的表現和功能仍然不清楚。 我們的研究顯示,與鄰近的非腫瘤組織相比,蛋白醣化酵素C1GALT1在高達百分之八十五的胰臟癌腫瘤中及胰臟癌多株細胞株中都會過度表現。蛋白醣化酵素C1GALT1的高表現與較差之無疾病存活期及較差之整體存活期相關(九十九位病患);抑制調控蛋白醣化酵素C1GALT1可抑制胰臟癌細胞惡性表徵如生長、移行、侵犯、侵襲,促進胰臟癌細胞凋亡並增加對化療藥物吉西他濱(Gemcitabine)之敏感性,降低胰臟癌細胞附著能力,阻礙胰臟癌細胞週期進行;相反的,蛋白醣化酵素C1GALT1的過度表現則增強了細胞的移行及侵犯;在皮下注射和胰腺原位注射的活體小鼠(NOD/SCID mice)模型實驗中,抑制蛋白醣化酵素C1GALT1可降低活體小鼠的胰臟癌腫瘤生長和減少胰臟癌細胞的轉移。 探討其機制,蛋白醣化酵素C1GALT1的降低顯著抑制了細胞與細胞外基質的粘附,這與局部粘附激化酵素(Focal adhesion kinase, FAK)在位點Y397、Y925兩處的磷酸化降低以及整合素(包括β1、αV、α5亞基)上的氧型聚醣變化有關。使用功能性阻斷抗體,我們確定整合素αV是蛋白醣化酵素C1GALT1調控胰臟癌細胞侵襲性的關鍵因素;蛋白醣化酵素C1GALT1調控抑制降低胰臟癌細胞中與凋亡相關因子的活性,並抑制多種受體酪氨酸激化酵素(RTK)的磷酸化。 結論,這項研究不僅揭示了蛋白醣化酵素C1GALT1可作為胰臟癌的潛在治療標的,而且還提供了對於氧型糖基化在整合素α亞基中的作用的新穎見解。 | zh_TW |
dc.description.abstract | Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death. PDAC is the most common (>95%) malignancy in pancreas, stands the 7th of all cancer mortalities and remains the most in progress in Taiwan or also stands the 4th universally. PDAC is even projected to be the 2nd of all cancer mortalities in 2030 in US. It had adhered to stability for the past 30 years without major breakthrough (5-year survival 3.8% to 10.0%). Surgical resection remains the most and only potential curative management but only 15-20% of patients are candidates. Even though, many of them have worse prognosis. New insight into the biology and genetics of pancreatic cancer is a unique entity of investigation in the breakthroughs of early diagnosis and further treatment. Glycosylation is the most abundant and diverse post-translational modification of proteins. Aberrant expression of glycans, such as Tn antigen and T antigen, are hallmark of most human cancers. Two major types of protein glycosylation are N- glycosylation and O-glycosylation. Mucin-type O-glycosylation, the most common type of O-glycosylation, is initiated when N-acetylgalactosamine (GalNAC) is added to form the Tn antigen, by GalNAc-transferases (GALNTs). The human GALNT family genes are differentially expressed in cells and have unique functions and considerable redundancy. Core 1 β1,3-galactosyltransferase (C1GALT1, or T synthase) catalyzes the transfer of Galactose to the Tn antigen to form T antigen. Altered glycosylation contributes to tumor progression and chemoresistance in many cancers. C1GALT1 is the key enzyme controlling the elongation of GalNAc-type O-glycosylation. Several studies have shown that up-regulation of Tn, T, and C1GALT1 contributes to clinicopathological features and malignant phenotypes in breast cancer, gastric cancer, colon cancer, hepatocellular carcinoma, head and neck cancer, ovarian cancer, and prostate cancer. However, the expression and function of Tn, T, and C1GALT1 in pancreatic cancer remain unclear. Here we showed that C1GALT1 was overexpressed in 85% (107/126) of PDAC tumors compared with adjacent non-tumor tissues. High expression of C1GALT1 was associated with poor disease-free and overall survival (n = 99). C1GALT1 knockdown using siRNA suppressed cell viability, migration, and invasion as well as increased gemcitabine sensitivity and arrested the cell cycle in PDAC cells. In contrast, C1GALT1 overexpression enhanced cell migration and invasion. In subcutaneous and pancreatic orthotopic injection models, C1GALT1 knockdown decreased tumor growth and metastasis of PDAC cells in NOD/SCID mice. Mechanistically, C1GALT1 knockdown dramatically suppressed ECM adhesion, which was associated with decreased phosphorylation of FAK at Y397/Y925 and changes in O-glycans on integrins including the β1, αv, and α5 subunits. Using functional blocking antibodies, we identified integrin αv as a critical factor in C1GALT1-mediated invasiveness of PDAC cells. C1GALT1 knockdown inhibited apoptosis-related activities and inhibited phosphorylation of several RTKs in PDAC cells. In conclusion, this study not only reveals that C1GALT1 could be a potential therapeutic target for PDAC but also provides novel insights into the role of O-glycosylation in the α subunits of integrins. | en |
dc.description.provenance | Made available in DSpace on 2021-06-17T08:12:07Z (GMT). No. of bitstreams: 1 U0001-2701202122363700.pdf: 16012045 bytes, checksum: cc152eb3334b5e18568020216e8931c8 (MD5) Previous issue date: 2021 | en |
dc.description.tableofcontents | 口試委員會審定書 ……………………………………………………………… i 序言及誌謝 ……………………………………………………………………… ii 中文摘要 ...……………………………………………………………………… iii Abstract ………………………………………………………………………… v Table of contents………………………………………………………………… vii Doctoral dissertation Chapter 1. Introduction ……………………………………………………… 1 1.1 Worldwide situation to confront pancreatic malignancies………………… 1 1.2 The unmet nees and state-of-the-art managements in pancreatic cancer … 2 1.3 Research trends and O-glycosylation in pancreatic cancer……………… 3 1.4 Desmoplastic stroma and tumor microenvironent………………………… 6 1.5 Importance of current study……………………………………………… 6 1.6 Hypothesis………………………………………………………………… 7 1.7 Study goals……………………………………………………………… 7 Chapter 2. Materials and Methods ………………………………………… 9 2.2 Clinical samples…………………………………………………………… 9 2.2 Immunohistochemical (IHC) staining…………………………………… 9 2.3 Cell lines and cell culture………………………………………………… 10 2.4 Transfection and plasmid constructs……………………………………… 11 2.5 Antibodies and reagents…………………………………………………… 12 2.6 Western blot analysis……………………………………………………… 14 2.7 Lectin pull-down assays…………………………………………………… 14 2.8 Flow cytometry…………………………………………………………… 15 2.9 MTT assay………………………………………………………………… 16 2.10 Transwell migration and Matrigel invasion assays……………………… 16 2.11 Cell spreading analysis…………………………………………………… 17 2.12 Cell adhesion assay……………………………………………………… 17 2.13 Immunoprecipitation and membrane protein extraction…………………… 17 2.14 In vivo mouse animal models…………………………………………… 18 2.15 Gene set enrichment analysis (GSEA) of cDNA microarray……………… 19 2.16 Statistical analysis……………………………………………………… 20 Chapter 3. Results …………………………………………………………… 21 3.1 C1GALT1 is overexpressed and correlated with poor survival in PDAC patients……………………………………………………………………… 21 3.2 C1GALT1 knockdown inhibits malignant behaviors in PDAC cells……… 22 3.3 C1GALT1 knockdown regulates cell cycle……………………………… 23 3.4 C1GALT1 overexpression enhances malignant behaviors in PDAC cells… 25 3.5 C1GALT1 overexpression enhances malignant behaviors in PDAC cells… 25 3.6 C1GALT1 knockdown inhibits tumor growth and metastasis in vivo…… 26 3.7 C1GALT1 knockdown suppresses cell-ECM adhesion in PDAC cells…… 26 3.8 C1GALT1 knockdown suppresses integrin-FAK signaling in PDAC cells…… 27 3.9 C1GALT1 knockdown alters O-glycans on integrins in PDAC cells……… 28 3.10 C1GALT1 knockdown suppresses cell-ECM adhesion and integrin-FAK signaling as well as alters O-glycans on integrins in PDAC cells……………… 28 3.11 Integrin αv is involved in C1GALT1-mediated invasion in PDAC cells…… 29 3.12 C1GALT1 knockdown regulates integrin associated functional genes…… 31 Chapter 4. Discussion ………………………………………………………… 32 4.1 C1GALT1, controlling the elongation of O-glycans, was overexpressed in PDAC and associated with survival………………………………………………… 32 4.2 Integrin αV is critical in C1GALT1-mediated invasiveness of PDAC…… 32 4.3 C1GALT1, a potential therapeutic target for PDAC, provides novel insights into O-glycosylation on ITG αV/5……...………….………………………………… 33 4.4 Complete ablation of C1GALT1 might be harmful……………………… 34 Chapter 5. Perspectives ……………………………………………………… 36 5.1 Our future work………………………………………………………… 36 5.2 Future directions………………………………………………………… 38 Chapter 6. References ………………………………………………………… 39 Chapter 7. Figures and Figure Lenends …………………………………… 45 Chapter 8. Tables …………………………………………………………… 99 Chapter 9. Abbreviation list ………………………………………………… 112 Chapter 10. Supplementary…………………………………………………… 115 | |
dc.language.iso | en | |
dc.title | 蛋白醣化酵素C1GALT1在胰臟癌的表現與功能 | zh_TW |
dc.title | Expression And Function of O-glycosyltransferase C1GALT1 in Pancreatic Cancer | en |
dc.type | Thesis | |
dc.date.schoolyear | 109-1 | |
dc.description.degree | 博士 | |
dc.contributor.author-orcid | 0000-0003-1960-1423 | |
dc.contributor.advisor-orcid | 黃敏銓(0000-0002-0704-3447) | |
dc.contributor.coadvisor | 田郁文(Yun-Wen Tien) | |
dc.contributor.coadvisor-orcid | 田郁文(0000-0002-9126-2705) | |
dc.contributor.oralexamcommittee | 李伯皇(Po-Huang Lee),黃俊升(Chiun-Sheng Huang),賴逸儒(I-Rue Lai),龔秀妮(Hsiu-Ni Kung),王淑慧(Shu-Huei Wang) | |
dc.subject.keyword | 胰臟癌,胰管腺癌,C1GALT1,氧型醣化作用,整合素,細胞外基質,胰腺星狀細胞, | zh_TW |
dc.subject.keyword | Pancreatic cancer,Pancreatic ductal adenocarcinoma (PDAC),Core 1 β1,3-galactosyltransferase (C1GALT1),O-glycosylation,Integrins,Extracellular matrix (ECM),Pancreatic stellate cell (PSC), | en |
dc.relation.page | 132 | |
dc.identifier.doi | 10.6342/NTU202100223 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2021-02-01 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | zh_TW |
顯示於系所單位: | 解剖學暨細胞生物學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
U0001-2701202122363700.pdf 目前未授權公開取用 | 15.64 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。