請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/96676完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 黃敏銓 | zh_TW |
| dc.contributor.advisor | Min-Chuan Huang | en |
| dc.contributor.author | 許子文 | zh_TW |
| dc.contributor.author | Tzu-Wen Hsu | en |
| dc.date.accessioned | 2025-02-20T16:29:20Z | - |
| dc.date.available | 2025-02-21 | - |
| dc.date.copyright | 2025-02-20 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-12-18 | - |
| dc.identifier.citation | 1. Bray, F., et al., Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 2018. 68(6): p. 394-424.
2. Katai, H., et al., Five-year survival analysis of surgically resected gastric cancer cases in Japan: a retrospective analysis of more than 100,000 patients from the nationwide registry of the Japanese Gastric Cancer Association (2001-2007). Gastric Cancer, 2018. 21(1): p. 144-154. 3. Orditura, M., et al., Treatment of gastric cancer. World J Gastroenterol, 2014. 20(7): p. 1635-49. 4. Tran, P.N., et al., PD-1 and PD-L1 as emerging therapeutic targets in gastric cancer: current evidence. Gastrointest Cancer, 2017. 7: p. 1-11. 5. Potapenko, I.O., et al., Glycan gene expression signatures in normal and malignant breast tissue; possible role in diagnosis and progression. Molecular Oncology, 2010. 4(2): p. 98-118. 6. Song, Z., Roles of the nucleotide sugar transporters (SLC35 family) in health and disease. Molecular Aspects of Medicine, 2013. 34(2): p. 590-600. 7. Fuster, M.M. and J.D. Esko, The sweet and sour of cancer: glycans as novel therapeutic targets. Nature Reviews Cancer, 2005. 5(7): p. 526-542. 8. Freitas, D., et al., O-glycans truncation modulates gastric cancer cell signaling and transcription leading to a more aggressive phenotype. EBioMedicine, 2019. 40: p. 349-362. 9. Mereiter, S., et al., Glycosylation in the Era of Cancer-Targeted Therapy: Where Are We Heading? Cancer Cell, 2019. 36(1): p. 6-16. 10. Pinho, S.S. and C.A. Reis, Glycosylation in cancer: mechanisms and clinical implications. Nature Reviews Cancer, 2015. 15(9): p. 540-555. 11. Hakomori, S. and R. Kannagi, Glycosphingolipids as tumor-associated and differentiation markers. J Natl Cancer Inst, 1983. 71(2): p. 231-51. 12. Zurawski, V.R., et al., Elevated serum CA 125 levels prior to diagnosis of ovarian neoplasia: Relevance for early detection of ovarian cancer. International Journal of Cancer, 1988. 42(5): p. 677-680. 13. Reis, C.A., et al., Alterations in glycosylation as biomarkers for cancer detection. J Clin Pathol, 2010. 63(4): p. 322-9. 14. Costa, A.F., et al., Targeting Glycosylation: A New Road for Cancer Drug Discovery. Trends in Cancer, 2020. 6(9): p. 757-766. 15. He, L., K. Vasiliou, and D.W. Nebert, Analysis and update of the human solute carrier (SLC) gene superfamily. Human Genomics, 2009. 3(2): p. 195. 16. Caffaro, C.E. and C.B. Hirschberg, Nucleotide Sugar Transporters of the Golgi Apparatus: From Basic Science to Diseases. Accounts of Chemical Research, 2006. 39(11): p. 805-812. 17. Ng, B.G., et al., SLC35A2‐CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals. Human Mutation, 2019. 18. Kot, M., et al., SLC35A2 Deficiency Promotes an Epithelial-to-Mesenchymal Transition-like Phenotype in Madin–Darby Canine Kidney Cells. Cells, 2022. 11(15): p. 2273. 19. Sun, X., et al., Comprehensive Analysis of SLC35A2 in Pan-Cancer and Validation of Its Role in Breast Cancer. Journal of Inflammation Research, 2023. Volume 16: p. 3381-3398. 20. Yang, X., et al., SLC35A2 expression drives breast cancer progression via ERK pathway activation. FEBS J, 2024. 291(7): p. 1483-1505. 21. Cheng, H., et al., Nucleotide sugar transporter SLC35A2 is involved in promoting hepatocellular carcinoma metastasis by regulating cellular glycosylation. Cell Oncol (Dordr), 2023. 46(2): p. 283-297. 22. Wang, Y., et al., Comprehensive analysis of transcriptome data and experimental identification show that solute carrier 35 member A2 (SLC35A2) is a prognostic marker of colorectal cancer. Aging, 2023. 23. Marsico, G., et al., Glycosylation and Integrin Regulation in Cancer. Trends in Cancer, 2018. 4(8): p. 537-552. 24. Desgrosellier, J.S. and D.A. Cheresh, Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer, 2010. 10(1): p. 9-22. 25. Peng, Z., et al., Prognostic Significance of MET Amplification and Expression in Gastric Cancer: A Systematic Review with Meta-Analysis. PLoS ONE, 2014. 9(1): p. e84502. 26. Sierra, J.C., et al., Epidermal growth factor receptor inhibition downregulates<i>Helicobacter pylori</i>-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut, 2018. 67(7): p. 1247-1260. 27. Teoh, S.T., M.P. Ogrodzinski, and S.Y. Lunt, UDP-glucose 6-dehydrogenase knockout impairs migration and decreases in vivo metastatic ability of breast cancer cells. Cancer Letters, 2020. 492: p. 21-30. 28. Zhang, Y. and J.M. Yang, Altered energy metabolism in cancer: a unique opportunity for therapeutic intervention. Cancer Biol Ther, 2013. 14(2): p. 81-9. 29. Stine, Z.E., et al., Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discov, 2022. 21(2): p. 141-162. 30. Zhang, Y., et al., The SLC transporter in nutrient and metabolic sensing, regulation, and drug development. J Mol Cell Biol, 2019. 11(1): p. 1-13. 31. Nwosu, Z.C., et al., Nutrient transporters: connecting cancer metabolism to therapeutic opportunities. Oncogene, 2023. 42(10): p. 711-724. 32. Zhou, Q., et al., Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies. Signal Transduction and Targeted Therapy, 2024. 9(1). 33. Yoo, H.C., et al., A Variant of SLC1A5 Is a Mitochondrial Glutamine Transporter for Metabolic Reprogramming in Cancer Cells. Cell Metabolism, 2020. 31(2): p. 267-283.e12. 34. Chen, P.-D., et al., Decreased B4GALT1 promotes hepatocellular carcinoma cell invasiveness by regulating the laminin-integrin pathway. Oncogenesis, 2023. 12(1). 35. Heo, Y.J., et al., Integrative Multi-Omics Approaches in Cancer Research: From Biological Networks to Clinical Subtypes. Mol Cells, 2021. 44(7): p. 433-443. 36. Caines, J.K., D.A. Barnes, and M.D. Berry, The Use of Seahorse XF Assays to Interrogate Real-Time Energy Metabolism in Cancer Cell Lines. Methods Mol Biol, 2022. 2508: p. 225-234. 37. Wang, W., et al., Cancer metabolites: promising biomarkers for cancer liquid biopsy. Biomark Res, 2023. 11(1): p. 66. 38. Anderson, N.M. and M.C. Simon, The tumor microenvironment. Current Biology, 2020. 30(16): p. R921-R925. 39. Kim, H.J. and S.C. Bae, Histone deacetylase inhibitors: molecular mechanisms of action and clinical trials as anti-cancer drugs. Am J Transl Res, 2011. 3(2): p. 166-79. 40. Verza, F.A., et al., Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy. Cancers, 2020. 12(6): p. 1664. 41. Sun, J., et al., Butyrate as a promising therapeutic target in cancer: From pathogenesis to clinic (Review). International Journal of Oncology, 2024. 64(4). 42. Berni Canani, R., M. Di Costanzo, and L. Leone, The epigenetic effects of butyrate: potential therapeutic implications for clinical practice. Clinical Epigenetics, 2012. 4(1): p. 4. 43. Zhang, Y., et al., Current treatment strategies targeting histone deacetylase inhibitors in acute lymphocytic leukemia: a systematic review. Frontiers in Oncology, 2024. 14. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/96676 | - |
| dc.description.abstract | 胃癌仍然是全球癌症相關死亡的主要原因之一，尤其在東亞地區的發病率居高不下。儘管診斷和治療技術有所進步，但預後仍然不佳，特別是對於晚期疾病患者而言，其高轉移率和治療抗性導致死亡率居高不下。因此，迫切需要鑑定新的生物標誌物和治療標靶來改善患者的預後。異常糖基化是癌症的一個標誌，並在腫瘤進展中發揮關鍵作用，包括轉移、免疫逃逸和化療抗性。SLC35A2 是一種負責糖基生物合成的 UDP-半乳糖轉運蛋白，已被發現參與調控糖基化過程，但其在胃腺癌中的作用尚不清楚。
在本研究中，我們通過分析公共數據庫及臨床組織，發現 SLC35A2 表達在胃癌中顯著降低，且低表達與臨床預後不良相關，包括晚期 TNM 分期、血管侵犯和遠端轉移。Kaplan-Meier 生存分析進一步確認，低 SLC35A2 表達是較差生存率的重要預測因子。功能性研究表明，SLC35A2 的基因調降或敲除會促進胃癌細胞的遷移及侵襲性行為，並在動物實驗中促進腫瘤生長及轉移。 蛋白組學分析顯示，SLC35A2 調控整合素及參與細胞外基質相互作用、血管生成和鐵死亡相關通路蛋白的半乳糖基化。RNA-seq 則進一步揭示了 SLC35A2 在調控低氧反應、代謝重編程和免疫調節基因中的關鍵作用。此外，表觀遺傳調控因子可恢復 SLC35A2 的表達，突顯其作為治療標靶的潛力。 綜合來看，我們的研究確立了 SLC35A2 作為胃癌進展的關鍵調節因子，並強調其作為生物標誌物的重要性，以及透過靶定 SLC35A2 關聯的分子機制來解決胃癌臨床需求的潛力。 | zh_TW |
| dc.description.abstract | Gastric cancer remains a leading cause of cancer-related mortality worldwide, with a high prevalence in East Asia. Despite advances in diagnosis and treatment, its prognosis remains poor, especially for patients with advanced-stage disease, due to high rates of metastasis and therapeutic resistance. There is an urgent need to identify novel biomarkers and therapeutic targets to improve patient outcomes. Aberrant glycosylation is a hallmark of cancer and plays a pivotal role in tumor progression, including metastasis, immune evasion, and chemoresistance. SLC35A2, a UDP-galactose transporter essential for glycan biosynthesis, has been implicated in regulating glycosylation processes; however, its role in gastric adenocarcinoma remains unclear. In this study, we analyzed public databases and patient tissues, revealing that SLC35A2 expression is significantly downregulated in gastric cancer and low SLC35A2 expression correlates with poor clinical outcomes, including advanced TNM stage, vascular invasion, and distant metastasis. Kaplan-Meier survival analysis confirmed that low SLC35A2 expression is a strong predictor of worse overall survival. Functional studies demonstrated that SLC35A2 knockdown or knockout enhances migratory and invasive behaviors of gastric cancer cells in vitro and promotes metastasis and tumor growth in vivo. Proteomic profiling revealed that SLC35A2 modulates galactosylation of integrins and proteins involved in ECM interactions, angiogenesis, and ferroptosis pathways. RNA-seq further highlighted SLC35A2-dependent regulation of hypoxia response, metabolic reprogramming, and immune modulation genes. Finally, epigenetic modulators restored SLC35A2 expression, underscoring its potential as a therapeutic target.
Collectively, our findings establish SLC35A2 as a critical regulator of gastric cancer progression and emphasize its value as a biomarker, as well as its relevance for addressing the unmet clinical need by targeting SLC35A2-associated molecular processes. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-02-20T16:29:20Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-02-20T16:29:20Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
誌謝 ii 中文摘要 iii ABSTRACT v CONTENTS vii LIST OF FIGURES x LIST OF TABLES xii Chapter 1 Introduction 1 1.1 Gastric cancer 1 1.2 Protein glycosylation 1 1.3 Glycosylation in cancer. 2 1.4 SLC35A2 solute carrier family 35 member A2 3 1.5 SLC35A2 in Cancer 4 1.6 Integrins Glycosylation in Cancer 5 1.7 RTK Glycosylation in Cancer 5 1.8 Metabolism in Cancer 6 Chapter 2 Methods and Materials 7 2.1 Patient samples 7 2.2 Immunohistochemistry 7 2.3 Cell culture 7 2.4 Transfection and plasmid construction 8 2.5 Knockout of SLC35A2 via CRISPR/Cas9 in AGS and MKN28 cells 8 2.6 Western blot 8 2.7 MTT assays 9 2.8 Phospho-receptor tyrosine kinase array assay 9 2.9 Migration (Transwell) and Invasion (Matrigel) assays 9 2.10 In vivo xenograft animal models 10 2.11 Flow cytometry 11 2.12 Lectin pull-down assay 11 2.13 Mass spectrometric analysis 11 2.14 Cell adhesion assay 12 2.15 RNA-seq 12 2.16 cDNA synthesis and real-time RT-PCR 13 2.17 Statistic 13 Chapter 3 Results 14 3.1 Low SLC35A2 expression predicts poor survival in gastric adenocarcinoma: analysis using public databases 14 3.2 Lower SLC35A2 expression level correlates with poor survival of patients with gastric adenocarcinoma 14 3.3 SLC35A2 regulates the malignant behaviors of gastric cancer cells 15 3.4 Effects of SLC35A2 knockout on tumor growth and metastasis in NOD/SCID and ASID mice 16 3.5 Proteomic analysis of SLC35A2-modified glycoproteins in gastric cancer cells 17 3.6 Effects of SLC35A2 on Integrin-Mediated Cell-ECM Adhesion in Gastric Cancer Cells 18 3.7 SLC35A2 and phospho-tyrosine kinase signaling in gastric Cancer 20 3.8 Impact of SLC35A2 on angiogenesis and metabolic reprogramming in Gastric Cancer 21 3.9 Exploring SLC35A2-dependent gene expression profiles through RNA-Seq in gastric Cancer 21 3.10 Generation of SLC35A2 knockout mouse gastric cancer cells using the CRISPR/Cas9 system 23 3.11 Regulation of SLC35A2 expression in gastric cancer cells by epigenetic modulators 23 Chapter 4 Discussion 25 REFERENCE 30 LIST OF FIGURES Figure 1. Prognostic significance of SLC35A2 expression in gastric cancer patients analyzed using public databases. 35 Figure 2. SLC35A2 expression in gastric cancer tissues: Immunostaining and comparison with paired non-Tumor tissues. 36 Figure 3. Kaplan–Meier survival analysis of SLC35A2 expression in gastric cancer. 37 Figure 4. Western Blot analysis of SLC35A2 expression and manipulation in gastric cancer cell lines. 38 Figure 5. Effects of SLC35A2 knockdown or overexpression on cell viability. 39 Figure 6. SLC35A2 promotes malignant phenotypes in gastric cancer cells. A Effects of SLC35A2 on migration. 40 Figure 7. Representative images of gastric cancer cells migration and invasion. 41 Figure 8. SLC35A2 knockout enhances malignant behaviors in AGS and MKN28 cells. 42 Figure 9. Representative images of gastric cancer cells migration and invasion. 43 Figure 10. Effects of SLC35A2 knockout on tumor growth and metastasis in NOD/SCID and ASID mice. 44 Figure 11. Knockout of SLC35A2 decreases overall galactsylation in gastric cancer cells. 45 Figure 12. Effects of SLC35A2 knockout on glactosylation of integrin V, integrin 6, integrin 1, and integrin 4 in AGS and MKN28 cells. 46 Figure 13. SLC35A2 knockout increase cell-extracellular matrix (ECM) adhesion in gastric cancer cells. 47 Figure 14. SLC35A2 overexpression inhibits cell-extracellular matrix (ECM) adhesion in gastric cancer cells. 48 Figure 15. Blockade of integrin αV or integrin β1 inhibits migration and invasion promoted by SLC35A2 knockout in gastric cancer cells. 49 Figure 16. Representative images of Gastric cancer cells migration and invasion blocked with an anti-integrin αV or anti-integrin β1 antibody. 50 Figure 17. Effects of SLC35A2 knockout on multiple phospho-RTKs. 51 Figure 18. Impact of SLC35A2 on angiogenesis in gastric cancer. 52 Figure 19. Impact of SLC35A2 on ferroptosis in gastric cancer. 53 Figure 20. Genomic analysis of SLC35A2 knockout in gastric cancer cells. 54 Figure 21. Generation of slc35a2 knockout mouse gastric cancer cells using the CRISPR/Cas9 system. 55 Figure 22. Regulation of SLC35A2 expression in gastric cancer cells by epigenetic modulators 56 LIST OF TABLES Table 1. Correlation between the mRNA expression of nucleotide sugar transporters with overall survival rate of patients with gastric cancer. 57 Table 2. Correlation between SLC35A2 intensity with clinicopathologic characteristics. 58 Table 3. Correlation between SLC35A2 intensity with intestinal-type gastric cancer patients' clinicopathologic characteristics. 59 Table 4. Correlation between SLC35A2 intensity with diffuse-type gastric cancer patients' clinicopathologic characteristics. 60 Table 5. Glycoproteins identified by Mass Spectrometry. 61 Table 6.Top 10 significant pathways associated with SLC35A2-regulated proteins analyzed using NCI-Nature PID. 62 | - |
| dc.language.iso | en | - |
| dc.subject | 糖基化 | zh_TW |
| dc.subject | 整合素 | zh_TW |
| dc.subject | 代謝重編程 | zh_TW |
| dc.subject | 胃癌 | zh_TW |
| dc.subject | SLC35A2 | zh_TW |
| dc.subject | metabolic reprogramming | en |
| dc.subject | Gastric cancer | en |
| dc.subject | SLC35A2 | en |
| dc.subject | Glycosylation | en |
| dc.subject | Integrin | en |
| dc.title | 探討尿苷二磷酸半乳糖運輸蛋白SLC35A2在胃癌中的表現及功能 | zh_TW |
| dc.title | Expression and function of UDP-galactose transporter SLC35A2 in gastric cancer | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-1 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 李柏居;王淑慧;龔秀妮 | zh_TW |
| dc.contributor.oralexamcommittee | Po-Chu Lee;Shu-Huei Wang;Hsiu-Ni Kung | en |
| dc.subject.keyword | 胃癌,SLC35A2,糖基化,整合素,代謝重編程, | zh_TW |
| dc.subject.keyword | Gastric cancer,SLC35A2,Glycosylation,Integrin,metabolic reprogramming, | en |
| dc.relation.page | 62 | - |
| dc.identifier.doi | 10.6342/NTU202404736 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2024-12-18 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | - |
| dc.date.embargo-lift | 2029-12-16 | - |
| 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 | |
|---|---|---|---|
| ntu-113-1.pdf 此日期後於網路公開 2029-12-16 | 3.37 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。