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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 李明學 | |
| dc.contributor.author | Shao-Wei Lan | en |
| dc.contributor.author | 藍紹瑋 | zh_TW |
| dc.date.accessioned | 2021-06-17T01:36:20Z | - |
| dc.date.available | 2027-08-01 | |
| dc.date.copyright | 2017-09-08 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-08-01 | |
| dc.identifier.citation | 1. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer Statistics, 2017. CA Cancer J Clin, 2017. 67(1): p. 7-30.
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DuBois, Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nature Reviews Cancer, 2001. 1(1): p. 11-21. 169. Marnett, L.J. and R.N. DuBois, COX-2: a target for colon cancer prevention. Annu Rev Pharmacol Toxicol, 2002. 42: p. 55-80. 170. Ogino, S., et al., Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin Cancer Res, 2008. 14(24): p. 8221-7. 171. Herrmann, C., et al., Sulindac sulfide inhibits Ras signaling. Oncogene, 1998. 17(14): p. 1769-76. 172. Li, X., S.S. Pathi, and S. Safe, Sulindac sulfide inhibits colon cancer cell growth and downregulates specificity protein transcription factors. BMC Cancer, 2015. 15: p. 974. 173. Williams, C.S., et al., Sulindac sulfide, but not sulindac sulfone, inhibits colorectal cancer growth. Neoplasia, 1999. 1(2): p. 170-6. 174. Milner, J.M., et al., Matriptase is a novel initiator of cartilage matrix degradation in osteoarthritis. Arthritis Rheum, 2010. 62(7): p. 1955-66. 175. Suzuki, M., et al., Inhibition of tumor invasion by genomic down-regulation of matriptase through suppression of activation of receptor-bound pro-urokinase. J Biol Chem, 2004. 279(15): p. 14899-908. 176. Uhland, K., Matriptase and its putative role in cancer. Cell Mol Life Sci, 2006. 63(24): p. 2968-78. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67531 | - |
| dc.description.abstract | 癌細胞的侵襲和轉移與人類癌症的惡化和病人的存活有強烈的相關性，在這篇研究中，我描述了間質蛋白酶(matriptase)在攝護腺癌和大腸直腸癌中的角色，包括: 1) 間質蛋白酶在第二型環氧合酶(COX-2)所誘導的攝護腺癌細胞侵襲和轉移中的角色; 2) 間質蛋白酶在表皮生長因子/表皮生長因子受體/K-Ras訊息所誘導的大腸直腸癌細胞侵襲中的角色。第一部分：慢性發炎對癌症的發展和惡化扮演了重要的角色。第二型環氧合酶所產生的前列腺素會造成發炎並且在攝護腺癌中常常伴隨著第二型環氧合酶的大量表現。我們想要去探討第二型環氧合酶是透過何種分子機制去促進攝護腺癌細胞侵襲和轉移。並且去探討第二型環氧合酶的抑制者在不同攝護腺癌惡化模式中的影響。結果顯示，在高侵襲的攝護腺癌細胞中，第二型環氧合酶和介白素1 (IL-1) 都有較高的表現，並且與間質蛋白酶有相關性。在攝護腺癌病人的檢體中第二型環氧合酶和間質蛋白酶的表現量也呈現正相關性。此外，大量表現第二型環氧合酶或是其下游產物前列腺素會造成間質蛋白酶的活化和攝護腺癌細胞的侵襲增加 ; 因此，抑制二型環氧合酶的表現可以抑制間質蛋白酶的活化和攝護腺癌細胞的侵襲。此外，在原位異種移植的老鼠模式中，利用希樂葆(Celebrex)和硫酸舒林酸(sulindac sulfide)抑制第二型環氧合酶所誘導的間質蛋白酶活化可以抑制非雄激素和第二型環氧合酶大量表現的攝護癌細胞(PC-3)侵襲，腫瘤生長和肺部轉移。這些結果顯示了，第二型環氧合酶/間質蛋白酶這條訊息貢獻了第二型環氧合酶大量表現和非雄激素的攝護腺癌細胞的侵襲，腫瘤生長和轉移。
第二部分：失調的表皮生長因子受體訊息已經被指出參與了大腸直腸癌細胞的侵襲和轉移。在這篇研究中，我探討了表皮生長因子的訊息是透過何種分子機制來促進大腸直腸癌細胞的侵襲。結果顯示，在侵襲能力較高的大腸直腸癌細胞中(KM12L4和KM12SM)，表皮生長因子受體的磷酸化和蛋白質的表現量與活化的間質蛋白酶皆高於侵襲力較差的大腸直腸癌細胞(KM12C)。此外，表皮生長因子可以透過PI3K/AKT的訊息傳遞誘導間質蛋白酶活化和大腸直腸癌細胞的侵襲。大量表現K-Ras(野生型，突變型G12D和突變型G13D)可以藉由活化間質蛋白酶來促進KM12C細胞的侵襲能力。大量表現間質蛋白酶可以促進大腸直腸癌細胞的侵襲力，然後，將間質蛋白酶的表現降低可以減少表皮生長因子和K-Ras所誘導的大腸直腸癌細胞的侵襲力。此外，大量表現持續活化的突變型K-Ras會使KM12C轉變成對表皮生長因子受體抑制者(afatinib)所抑制的細胞侵襲和間質蛋白酶的活化有抗性。抑制PI3K或MEK可以減少K-Ras所誘導的大腸直腸癌細胞侵襲力。這些結果顯示了，間質蛋白酶參與由表皮生長因子/K-Ras/AKT訊息所誘導的大腸直腸癌細胞侵襲作用當中。 總結來說，間質蛋白酶的活化在促進攝護腺癌和大腸直腸癌的惡化過程中扮演了重要的角色，並經由兩種不同的訊息傳遞所活化。在攝護腺癌細胞中是經由第二型環氧合酶/間質蛋白酶，在大腸直腸癌中則是經由表皮生長因子受體/K-Ras/AKT/間質蛋白酶。因此，間質蛋白酶對治療具有癌化變異(例如：第二型環氧合酶，表皮生長因子受體，K-Ras，PI3K…等等)的癌症，將是一個具有潛力的治療標靶。 | zh_TW |
| dc.description.abstract | Cancer cell invasion and metastasis are strongly associated human cancer progression and patients’ survival. In this study, two main projects were performed to address the roles of pericellular protease matriptase in 1) cyclooxygenase-2 (COX-2)-induced prostate cancer (PCa) cell invasion and metastasis, and 2) EGF/EGFR/K-Ras-induced colorectal cancer cell invasion.
Part I: Role of matriptase in COX-2-induced PCa progression- Chronic inflammation plays an important role in cancer development and progression. COX-2 is a key enzyme in generating prostaglandins causing inflammation in PCa. We aim to investigate the molecular mechanism of how COX-2 promotes PCa cell invasion and metastasis and to evaluate the effect of COX-2 inhibitors on PCa progression. Our results showed that the expression of COX-2 and Interleukin 1 (IL-1) was upregulated in highly invasive PCa cells and was correlated with the activated levels of matriptase. The expression levels of COX-2 were increased and correlated with matriptase levels in PCa specimens. Moreover, results showed that COX-2 overexpression or a COX-2 downstream product Prostaglandin E2 (PGE2) caused an increase in matriptase activation and PCa cell invasion, whereas COX-2 silencing antagonized matriptase activation and cell invasion. In addition, the inhibition of COX-2-mediated matriptase activation by Celebrex and sulindac sulfide suppressed the androgen-independent and COX-2-overexpressing PC-3 cell invasion, tumor growth and lung metastasis in an orthotopic xenograft model. These results together indicate that COX-2/matriptase signaling contributes to the invasion, tumor growth and metastasis of COX-2-overexpressing and androgen-independent PCa cells. Part II: Role of matriptase in EGFR/K-Ras-induced colorectal cancer cell invasion and progression- Dysregulation of EGFR signaling have been shown to be involved in colorectal cancer cell invasion and metastasis. In this study, I explored the molecular mechanism how EGF signaling promoted colorectal cancer cell invasion. The results showed the phosphorylation and protein levels of EGFR and activated level of matritpase were increased in highly invasive colorectal cancer KM12L4 and KM12SM cells, compared with parental KM12C cells. Moreover, EGF can induce matriptase activation and colorectal cancer cell invasion through PI3K/AKT rather than RAF/MEK/Erk signaling. K-Ras overexpression (wild-type, G12D and G13D) can enhance KM12C cells invasion through matriptase activation. Matriptase overexpression promoted colorectal cancer cell invasion, whereas matriptase knockdown reduced EGF- and K-Ras-induced colorectal cancer cell invasion. Furthermore, the overexpression of constitutively active K-Ras mutants transformed KM12C cells with resistance to the inhibitory effect of afatinib on the cell invasion and matriptase activation. The inhibition of PI3K or MEK can reduce K-Ras-induced colorectal cancer cell invasion, suggesting that both signal pathways are involved in K-Ras-induced colorectal cancer cell invasion. In summary, the results together indicate that matriptase is involved in EGFR/K-Ras/AKT signaling-induced colorectal cancer cell invasion. In summary, matriptase mediates inflammatory COX-2 signaling in prostate cancer and EGFR/K-Ras/AKT signaling in colorectal cancer, leading to promoting prostate and colorectal cancer cell invasion and progression. Thus, matriptase might serve as a potential therapeutic target for drug development against human cancers with oncogenic mutations of COX-2, EGFR, K-Ras, PI3K etc. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T01:36:20Z (GMT). No. of bitstreams: 1 ntu-106-F98442013-1.pdf: 21259651 bytes, checksum: fe23cc6a4ec094a1d4735e37842ff60d (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 誌謝 i
中文摘要 iii Abstract vi Chapter 1. Introduction 1 1.1 Prostate cancer 2 1.2 Cyclooxygenase-2 (COX-2) 3 1.3 Non-steroidal anti-inflammatory drugs 5 1.4 Colorectal cancer 6 1.5 EGFR signaling pathway and colorectal cancer progression 9 1.6 K-Ras signaling 12 1.7 Matriptase 14 1.8 The purpose of this study 17 Chapter 2. Materials and Methods 18 Chapter 3. Results 30 Section 1 30 3.1.1 Correlation of COX-2 signaling with matriptase activation in human prostate cancer (PCa) invasion progression models. 31 3.1.2 COX-2 and matriptase were overexpressed in PCa patients’ tissues. 32 3.1.3 Involvement of COX-2 in matriptase activation and PCa cell invasion. 33 3.1.4 Prostaglandin E2 (PGE2) induced PC3 cell invasion and matriptase activation. 34 3.1.5 Effect of COX-2 inhibition by NSAIDs on matriptase in PC-3 cells. 35 3.1.6 Effect of Celebrex and sulindac sulfide on the viability and invasion of PCa cells. 36 3.1.7 Inhibitory effect of Celebrex on matriptase-overexpressing PC-3 cell migration, invasion and matriptase activation. 37 3.1.8 Role of COX-2 in Celebrex-suppressed PC-3 cell invasion and matriptase activation. 37 3.1.9 Targeting the COX-2/matriptase axis suppressed tumor growth and metastasis in a PCa orthotopic xenograft model. 38 Chapter 3. Results 40 Section 2 40 3.2.1 Colorectal cancer cell progression model. 41 3.2.2 In vitro characteristics of KM12C, KM12-L4 and KM12-SM cells 41 3.2.3 Serine proteases play an important role in colorectal cancer cell invasion 43 3.2.4 EGF induces colorectal cancer cell invasion and matriptase activation. 45 3.2.5 Matriptase is involved in EGF-induced colorectal cancer cell invasion. 46 3.2.6 K-Ras induces colorectal cancer cell invasion and matriptase activation. 48 3.2.7 Effects of Afatinib on constitutively active K-Ras-induced matriptase activation and colorectal cancer cell inavasion. 50 3.2.8 Effect of matriptase knockdown on EGF- and K-Ras-induced KM12C cell invasion. 50 3.2.9 Role of EGFR’s downstream signal molecules (K-Ras, Akt and Erk) in matriptase activation and colorectal cancer cell invasion. 51 3.2.10 Correlation of K-Ras protein levels with the levels of activated matriptase and total matriptase in human archival colorectal cancer specimens. 52 Chapter 4. Discussion 54 Chapter 5. Figures 64 Section 1 64 Figure 1. Establishment of prostate cancer (PCa) PC-3 cell progression model and analysis of COX-2, IL-1β and matriptase expression in PCa cell progression models. 66 Figure 2. Effect of COX-2 on matriptase activation and cell invasion. 70 Figure 3. Effect of PGE2 on matriptase activation and the cell mobility in PC3 cells. 72 Figure 4. Role of matriptase in PGE2-induced PC-3 cell invasion. 74 Figure 5. Analysis of EP receptors in matriptase activation of PC-3 cells. 75 Figure 6. Effect of COX-2 inhibitors on matriptase in PC-3 cells. 78 Figure 7. Effect of Celebrex on the cell viability, migration, invasion and matriptase of DU-145 and LNCaP cells. 80 Figure 8. Roles of COX-2/matriptase in cell migration, invasion and matriptase activation of PC-3 cells. 84 Figure 9. Roles of COX-2/PGE2 in cell migration, invasion and matriptase activation of PC-3 cells. 86 Figure 10. COX-2 inhibitors suppressed tumor growth and metastasis in a PC3 orthotopic xenograft model. 89 Figure 11. Schematic diagram of section 1. 91 Chapter 5. Figures 92 Section 2 92 Figure 1. Establishment of human colorectal cancer progression model. 94 Figure 2. Analysis of the in vitro characteristics of KM12C, KM12-L4 and KM12-SM cells. 95 Figure 3. Examination of the roles of serine protease and metalloprotease in the colorectal cancer cell invasion. 97 Figure 4. EGF induced colorectal cancer cell invasion and matriptase activation. 100 Figure 5. Matriptase was involved in EGF-induced colorectal cancer cell invasion. 104 Figure 6. K-Ras induced colorectal cancer cell invasion and matriptase activation. 108 Figure 7. Effects of Afatinib on K-Ras-induced matriptase activation and colorectal cancer cell invasion. 112 Figure 8. Effects of matriptase knockdown on EGF- and K-Ras-induced KM12C cell invasion. 115 Figure 9. Analyses of the Akt and Erk roles in EGF- and K-Ras-induced matriptase activation and KM12C cell invasion. 117 Figure 10. Correlation of K-Ras protein levels with the levels of activated matriptase and total matriptase in archival human colorectal cancer specimens. 120 Chapter 6. References 122 Publications 135 | |
| dc.language.iso | zh-TW | |
| dc.subject | 表皮生長因子受體 | zh_TW |
| dc.subject | 攝護腺癌 | zh_TW |
| dc.subject | 間質蛋白? | zh_TW |
| dc.subject | 大腸直腸癌 | zh_TW |
| dc.subject | 第二型環氧合? | zh_TW |
| dc.subject | K-Ras | en |
| dc.subject | Matriptase | en |
| dc.subject | prostate cancer | en |
| dc.subject | COX-2 | en |
| dc.subject | colorectal cancer | en |
| dc.subject | EGFR | en |
| dc.title | 間質蛋白酶在攝護腺癌與大腸直腸癌中所扮演的角色 | zh_TW |
| dc.title | Role of matriptase in prostate and colorectal cancer | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 張震東,林泰元,華國泰,黃祥博 | |
| dc.subject.keyword | 間質蛋白?,攝護腺癌,第二型環氧合?,大腸直腸癌,表皮生長因子受體, | zh_TW |
| dc.subject.keyword | Matriptase,prostate cancer,COX-2,colorectal cancer,EGFR,K-Ras, | en |
| dc.relation.page | 135 | |
| dc.identifier.doi | 10.6342/NTU201702373 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-08-01 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 生物化學暨分子生物學研究所 | zh_TW |
| 顯示於系所單位： | 生物化學暨分子生物學科研究所 | |
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