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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89211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 | 葉庭芝 | zh_TW |
| dc.contributor.author | Ting-Chih Yeh | en |
| dc.date.accessioned | 2023-09-05T16:07:41Z | - |
| dc.date.available | 2023-11-09 | - |
| dc.date.copyright | 2023-09-05 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-08-02 | - |
| dc.identifier.citation | 1. Webb, P.M. and S.J. Jordan, Epidemiology of epithelial ovarian cancer. Best Pract Res Clin Obstet Gynaecol, 2017. 41: p. 3-14.
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Am J Pathol, 2011. 179(3): p. 1394-404. 10. Chang, H.H., et al., beta-1,4-Galactosyltransferase III enhances invasive phenotypes via beta1-integrin and predicts poor prognosis in neuroblastoma. Clin Cancer Res, 2013. 19(7): p. 1705-16. 11. Liu, C.H., et al., C1GALT1 promotes invasive phenotypes of hepatocellular carcinoma cells by modulating integrin beta1 glycosylation and activity. PLoS One, 2014. 9(8): p. e94995. 12. Chen, C.H., et al., beta-1,4-Galactosyltransferase III suppresses beta1 integrin-mediated invasive phenotypes and negatively correlates with metastasis in colorectal cancer. Carcinogenesis, 2014. 35(6): p. 1258-66. 13. Chen, C.H., et al., MUC20 promotes aggressive phenotypes of epithelial ovarian cancer cells via activation of the integrin beta1 pathway. Gynecol Oncol, 2016. 140(1): p. 131-7. 14. Kuo, T.C., et al., C1GALT1 high expression is associated with poor survival of patients with pancreatic ductal adenocarcinoma and promotes cell invasiveness through integrin alphav. Oncogene, 2021. 40(7): p. 1242-1254. 15. Carduner, L., et al., Cell cycle arrest or survival signaling through alphav integrins, activation of PKC and ERK1/2 lead to anoikis resistance of ovarian cancer spheroids. Exp Cell Res, 2014. 320(2): p. 329-42. 16. Carduner, L., et al., Ascites-induced shift along epithelial-mesenchymal spectrum in ovarian cancer cells: enhancement of their invasive behavior partly dependant on alphav integrins. Clin Exp Metastasis, 2014. 31(6): p. 675-88. 17. Sawada, K., et al., Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target. Cancer Res, 2008. 68(7): p. 2329-39. 18. Shen, Y., et al., Fibrillar type I collagen matrices enhance metastasis/invasion of ovarian epithelial cancer via beta1 integrin and PTEN signals. Int J Gynecol Cancer, 2012. 22(8): p. 1316-24. 19. Neubert, P. and S. Strahl, Protein O-mannosylation in the early secretory pathway. Curr Opin Cell Biol, 2016. 41: p. 100-8. 20. Vester-Christensen, M.B., et al., Mining the O-mannose glycoproteome reveals cadherins as major O-mannosylated glycoproteins. Proc Natl Acad Sci U S A, 2013. 110(52): p. 21018-23. 21. Larsen, I.S.B., et al., Multiple distinct O-Mannosylation pathways in eukaryotes. Curr Opin Struct Biol, 2019. 56: p. 171-178. 22. Larsen, I.S.B., et al., Discovery of an O-mannosylation pathway selectively serving cadherins and protocadherins. Proc Natl Acad Sci U S A, 2017. 114(42): p. 11163-11168. 23. Larsen, I.S.B., et al., Mammalian O-mannosylation of cadherins and plexins is independent of protein O-mannosyltransferases 1 and 2. J Biol Chem, 2017. 292(27): p. 11586-11598. 24. Eisenhaber, B., et al., Conserved sequence motifs in human TMTC1, TMTC2, TMTC3, and TMTC4, new O-mannosyltransferases from the GT-C/PMT clan, are rationalized as ligand binding sites. Biol Direct, 2021. 16(1): p. 4. 25. Sunryd, J.C., et al., TMTC1 and TMTC2 are novel endoplasmic reticulum tetratricopeptide repeat-containing adapter proteins involved in calcium homeostasis. J Biol Chem, 2014. 289(23): p. 16085-99. 26. Carvalho, S., et al., O-mannosylation and N-glycosylation: two coordinated mechanisms regulating the tumour suppressor functions of E-cadherin in cancer. Oncotarget, 2016. 7(40): p. 65231-65246. 27. Chen, X., Q. Zhang, and T. Chekouo, Filtering High-Dimensional Methylation Marks With Extremely Small Sample Size: An Application to Gastric Cancer Data. Front Genet, 2021. 12: p. 705708. 28. Makboul, R., et al., Transmembrane and Tetratricopeptide Repeat Containing 4 Is a Novel Diagnostic Marker for Prostate Cancer with High Specificity and Sensitivity. Cells, 2021. 10(5). 29. Lengyel, E., Ovarian cancer development and metastasis. Am J Pathol, 2010. 177(3): p. 1053-64. 30. Zent, R. and A. Pozzi, Cell-extracellular matrix interactions in cancer. 2010, New York: Springer. xii, 314 p. 31. Siegel, R.L., et al., Cancer Statistics, 2021. CA Cancer J Clin, 2021. 71(1): p. 7-33. 32. Choi, Y.P., et al., Targeting ILK and beta4 integrin abrogates the invasive potential of ovarian cancer. Biochem Biophys Res Commun, 2012. 427(3): p. 642-8. 33. Lee, J.G., et al., Mutant p53 promotes ovarian cancer cell adhesion to mesothelial cells via integrin beta4 and Akt signals. Sci Rep, 2015. 5: p. 12642. 34. Arimori, T., et al., Structural mechanism of laminin recognition by integrin. Nat Commun, 2021. 12(1): p. 4012. 35. Ahmed, N., et al., Role of integrin receptors for fibronectin, collagen and laminin in the regulation of ovarian carcinoma functions in response to a matrix microenvironment. Clin Exp Metastasis, 2005. 22(5): p. 391-402. 36. Stewart, R.L. and K.L. O'Connor, Clinical significance of the integrin alpha6beta4 in human malignancies. Lab Invest, 2015. 95(9): p. 976-86. 37. Kenny, H.A., et al., Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion. J Clin Invest, 2014. 124(10): p. 4614-28. 38. Marsico, G., et al., Glycosylation and Integrin Regulation in Cancer. Trends Cancer, 2018. 4(8): p. 537-552. 39. Hang, Q., et al., N-Glycosylation of integrin alpha5 acts as a switch for EGFR-mediated complex formation of integrin alpha5beta1 to alpha6beta4. Sci Rep, 2016. 6: p. 33507. 40. Zhang, C., et al., Knockdown of C1GalT1 inhibits radioresistance of human esophageal cancer cells through modifying beta1-integrin glycosylation. J Cancer, 2018. 9(15): p. 2666-2677. 41. Liu, L., et al., TRPM7 promotes the epithelial-mesenchymal transition in ovarian cancer through the calcium-related PI3K / AKT oncogenic signaling. J Exp Clin Cancer Res, 2019. 38(1): p. 106. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/89211 | - |
| dc.description.abstract | 研究目的:卵巢癌是目前最致命的婦科惡性腫瘤。儘管O型甘露醣基轉移酶TMTC1在卵巢癌中有過度表現的情形，在卵巢癌中所扮演的角色仍然是未知的。
研究方法:透過免疫組織化學染色方法分析檢體中TMTC1的表現。經由卵巢癌細胞生長、移動、侵襲能力以及貼附的實驗，評估體外環境中的惡性特質。體內環境中的惡性特質則是藉由腹膜轉移測定。ConA的pull-down以及醣蛋白質體技術則是用於鑑定TMTC1的受體。 研究結果:與鄰近的正常卵巢組織相比，TMTC1在卵巢癌組織中有過度表現的狀況，且TMTC1過度表現與卵巢癌患者的不良預後明顯相關。降低TMTC1在卵巢癌細胞中的表現量，能夠抑制卵巢癌細胞的生長、移動、侵襲能力以及貼附。裸鼠的腹膜轉移測定中我們發現降低TMTC1的表現量，能夠抑制腹膜腫瘤的生長和轉移。另一方面，增加TMTC1在卵巢癌細胞中的表現量則是促進這些惡性特質。integrin β1以及β4是TMTC1的受體，TMTC1造成的移動與侵襲能力會被integrin β1或β4的siRNA阻斷。 研究結論: TMTC1主要是透過調控integrins β1和β4的O型甘露醣基化而促進卵巢癌的細胞侵襲且是具有潛力的卵巢癌症治療分子標靶。 | zh_TW |
| dc.description.abstract | Objective. Among gynecological malignancies, the most lethal tumor is ovarian cancer. Although O-mannosyltransferase transmembrane and tetratricopeptide repeat containing 1 (TMTC1) exhibits high expression levels in ovarian cancer, no studies have investigated its precise role in ovarian cancer.
Methods. TMTC1 expression levels in clinical samples were examined by immunohistochemistry. Malignant properties of ovarian cancer cells were evaluated by MTT, transwell migration, Matrigel invasion, and adhesion assays in vitro and peritoneal xenograft assay in vivo. Protein substrates of TMTC1 were identified using Concanavalin A (ConA) pull-down assay and glycoproteomic analysis. Results. In ovarian cancer patients, the expression of TMTC1 was found to be higher in the cancerous tissue specimens compared to the corresponding adjacent normal tissues. The high expression level of TMTC1 was significantly correlated with a poor prognosis among patients diagnosed with ovarian cancer. Knockdown of TMTC1 inhibited ovarian cancer cell viability, migration, invasion, and cell-laminin adhesion in vitro, in addition to inhibiting peritoneal tumor growth and metastasis in vivo. Conversely, TMTC1 overexpression promoted these malignant properties. Through mass spectrometry, integrins β1 and β4 were identified as new protein substrates of TMTC1. Notably, knockdown of integrin β1 or β4 was sufficient to reverse the TMTC1-induced migration and invasion. Conclusions. TMTC1 facilitates the invasive behaviors of ovarian cancer cells mainly via integrins β1 and β4, making it a promising and potential target for therapeutic interventions in ovarian cancer. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-05T16:07:41Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-09-05T16:07:41Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | Contents
Signatures of Committees…………………………………………...………………….Ⅰ Acknowledgement…………………………………………………...……………........Ⅱ Abstract (Chinese)……...…………..…………..………………………………...……Ⅲ Abstract (English) …………………………...…………….………...………...….......Ⅳ Chapter Ⅰ. Introduction……...……………………………...………...……………......1 1.1 Ovarian cancer…………….……………………………….…………...……………1 1.2 Integrin……………………………………………………………………………….3 1.3 O-Man glycosylation…………………..…………………………..….…..…………5 1.4 TMTC1………………………………………………………….…………..…….…6 Chapter Ⅱ. Materials and Methods……………………………………………....……7 2.1 Cell lines and culture………………………………………………………...….……7 2.2 Antibody generation and immunohistochemistry (IHC)………………….….....……8 2.3 Real-time RT-PCR analysis………..……………………………………….…..……9 2.4 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT)……...9 2.5 Transfection and plasmid construction.…………………………………….....……10 2.6 Migration and invasion assay………………………….....……..….……..……..…11 2.7 Adhesion assay……………………………………………………………………..12 2.8 LC-MS/MS analysis and database search…………………………………….……12 2.9 ConA pull-down assay……………………………………...………………………13 2.10 Western blot analysis……………………………………………………...………14 2.11 Peritoneal metastasis assay…………………………………...………...…………15 2.12 Statistical analysis…………………………………………………………………15 Chapter Ⅲ. Results………………...………………………….…………...…………16 3.1 Overexpression of TMTC1 in ovarian cancer..………………………………..……16 3.2 Elevated TMTC1 expression level is correlated with poorer prognosis among patients diagnosed with ovarian cancer.…………………………………….…………………...16 3.3 TMTC1 expresses in ovarian cancer cells………………………………...…....…...17 3.4 TMTC1 promotes cell viability in ovarian cancer cells…………………...…...…...18 3.5 TMTC1 promotes transwell migration and Matrigel invasion in ovarian cancer cells…………………………………………………………………………......….…...18 3.6 TMTC1 enhances ovarian cancer cells’ adhesion to laminin.…………..…..….…...19 3.7 TMTC1 enhances FAK and AKT phosphorylation….……………...……..…….....19 3.8 The integrins β1 and β4 O-Man glycosylation are modified by TMTC1 in ovarian cancer cells……………………………………………………………………………...20 3.9 The involvement of EPHA2 in the TMTC1-regulated malignant phenotypes was found to be insignificant.……..………………………………………….……….…......22 3.10 TMTC1 had no impact on the O-Man glycosylation of integrins α3 and α6.……....23 3.11 TMTC1 induced a slight enhancement in the heterodimerization between integrin α6 and β1……………………………………………….…………………………………..23 3.12 TMTC1 did not affect the mRNA expression of MGAT5.….…….………………...23 3.13 ITGB1 knockdown can reverse the TMTC1-induced effects on malignant phenotypes.…………………………………………….……….……….………....…...24 3.14 ITGB4 knockdown can reverse the TMTC1-induced effects on malignant phenotypes.…………………………………………………………………………......25 3.15 TMTC1 enhances the growth and metastasis of peritoneal tumors in vivo….…....25 3.16 TMTC1 docking results and the therapeutic potential of targeting TMTC1 in human ovarian cancer treatment..……………………………………………...…..…………...26 Chapter Ⅳ. Discussion…………………………………….……….…….…………...27 4.1 TMTC1 plays important roles in ovarian cancer……………….…….…..………...27 4.2 TMTC1 specifically modifies integrins β1 and β4 to promote the malignant behavior of ovarian cancer cells………………………………………….……………….……...28 4.3 O-Man glycosylation modulates the activities of integrins β1 and β4….…….……29 4.4 The regulation of ovarian cancer cell invasiveness by TMTC1 is unlikely to be mediated through its role in regulating calcium levels.……………………..…..……...30 4.5 Targeting TMTC1 holds promise as a therapeutic strategy for ovarian cancer..……31 References……………………………………………………………………………...32 Appendix…………………..…………………………………………….…………...68 | - |
| dc.language.iso | en | - |
| dc.subject | integrin β4 | zh_TW |
| dc.subject | integrin β1 | zh_TW |
| dc.subject | 卵巢癌 | zh_TW |
| dc.subject | O型甘露醣基化 | zh_TW |
| dc.subject | TMTC1 | zh_TW |
| dc.subject | integrin β4 | en |
| dc.subject | TMTC1 | en |
| dc.subject | O-Man glycosylation | en |
| dc.subject | Ovarian cancer | en |
| dc.subject | integrin β1 | en |
| dc.title | TMTC1透過integrins β1和β4促進卵巢癌細胞侵襲 | zh_TW |
| dc.title | TMTC1 promotes invasiveness of ovarian cancer cells through integrins β1 and β4 | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.coadvisor | 陳啓豪 | zh_TW |
| dc.contributor.coadvisor | Chi-Hau Chen | en |
| dc.contributor.oralexamcommittee | 劉烱輝;王淑慧 ;龔秀妮 | zh_TW |
| dc.contributor.oralexamcommittee | Chiung-Hui Liu ;Shu-Huei Wang;Hsiu-Ni Kung | en |
| dc.subject.keyword | TMTC1,,O型甘露醣基化,卵巢癌,integrin β1,integrin β4, | zh_TW |
| dc.subject.keyword | TMTC1,O-Man glycosylation,Ovarian cancer,integrin β1,integrin β4, | en |
| dc.relation.page | 69 | - |
| dc.identifier.doi | 10.6342/NTU202302473 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2023-08-02 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 解剖學暨細胞生物學研究所 | - |
| 顯示於系所單位： | 解剖學暨細胞生物學科所 | |
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