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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/68126完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 蔡孟勳 | |
| dc.contributor.author | Che-Yu Liao | en |
| dc.contributor.author | 廖哲妤 | zh_TW |
| dc.date.accessioned | 2021-06-17T02:13:05Z | - |
| dc.date.available | 2021-01-04 | |
| dc.date.copyright | 2018-01-04 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-12-07 | |
| dc.identifier.citation | Alam, J., and Cook, J.L. (2007). How many transcription factors does it take to turn on the heme oxygenase-1 gene? Am J Respir Cell Mol Biol 36, 166-174.
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Yanagawa, T., Omura, K., Harada, H., Nakaso, K., Iwasa, S., Koyama, Y., Onizawa, K., Yusa, H., and Yoshida, H. (2004). Heme oxygenase-1 expression predicts cervical lymph node metastasis of tongue squamous cell carcinomas. Oral Oncol 40, 21-27. Yazdani, U., and Terman, J.R. (2006). The semaphorins. Genome Biol 7, 211. Yoshida, A., Kohno, T., Tsuta, K., Wakai, S., Arai, Y., Shimada, Y., Asamura, H., Furuta, K., Shibata, T., and Tsuda, H. (2013). ROS1-rearranged lung cancer: a clinicopathologic and molecular study of 15 surgical cases. The American journal of surgical pathology 37, 554-562. Zhou, Q., Gallagher, R., Ufret-Vincenty, R., Li, X., Olson, E.N., and Wang, S. (2011). Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23∼ 27∼ 24 clusters. Proc Natl Acad Sci 108, 8287-8292. Zhou, Z.h., Rao, J., Yang, J., Wu, F., Tan, J., Xu, S.l., Ding, Y., Zhan, N., Hu, X.g., and Cui, Y.h. (2015). SEMA3F prevents metastasis of colorectal cancer by PI3K–AKT‐dependent down‐regulation of the ASCL2–CXCR4 axis. J Pathol 236, 467-478. Zhu, X., Huang, S., Zeng, L., Ma, J., Sun, S., Zeng, F., Kong, F., and Cheng, X. (2017). HMOX-1 inhibits TGF-beta-induced epithelial-mesenchymal transition in the MCF-7 breast cancer cell line. Int J Mol Med 40, 411-417. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/68126 | - |
| dc.description.abstract | 肺癌是所有癌症中致死率最高的，而肺癌早期發現及治療是全球目前的挑戰。其中非小細胞肺癌佔了所有肺癌病例的85%。儘管近幾年在診斷和治療方面進步了很多，但是肺癌的5年生存率依然很差，而且約有一半的肺癌細胞具轉移性，一旦肺癌細胞發生轉移，肺癌病患的死亡率將增加到90％以上，所以了解肺癌轉移的機制將有助於提高肺癌治療效果。在我們先前的研究中發現，Semaphorin6A (SEMA6A)的表現量在肺癌組織中是下降的，此外發現在肺癌細胞株中表現SEMA6A可以誘發細胞凋亡及抑制細胞的生長，也可以減少細胞移動的現象，進而推測SEMA6A可能在肺癌中扮演重要的角色及可能作為肺癌診斷的分子標誌物。本篇研究的目的是探討SEMA6A所調控的癌症細胞轉移機制。我們將SEMA6A大量表現在H1299肺癌細胞株後，以生物晶片實驗結果及Ingenuity Pathway Analysis (IPA)分析篩選出可能參與SEMA6A調控的細胞遷移基因。接著利用基因調控、細胞穿膜試驗及傷口癒合試驗鎖定並驗證這些基因的上下游關係。結果顯示血红素加氧酶1 ( heme oxygenase-1，HMOX1)基因在大量表現SEMA6A的H1299細胞後基因表現量會被上升且與細胞移動有關係。隨後發現HMOX1大量表現的H1299細胞，其細胞移動能力會下降；相反的，利用shRNA抑制HMOX1表現會增加細胞移動能力。若在大量表現SEMA6A細胞中同時抑制HMOX1，則會使SEMA6A抑制細胞移動能力的效果被抵消。此外，NF-E2相關因子2 (Nuclear Factor Erythroid 2-related Factor 2，NRF2)的表現量也發現在大量表現SEMA6A細胞中被上調，NRF2是已被報導可以調控HMOX1的上游基因。在此研究中發現，抑制NRF2時HMOX1的表現量同時也會被抑制，且增加細胞的移動能力。同樣的，在大量表現SEMA6A細胞同時抑制NRF2表現量的細胞中發現，HMOX1的表現量無法上調，進而使減少細胞移動能力的效果減弱，因此證明SEMA6A透過NRF2來上調HMOX1的表現來壓抑H1299細胞移動能力。最後，在大量表現SEMA6A細胞並同時抑制HMOX1的細胞中發現，會減弱由SEMA6A所上調的胰島素樣生長因子結合蛋白3 (Insulin Like Growth Factor Binding Protein 3，IGFBP3)及下調的尿激酶型血纖維蛋白溶解酶原活化因子(Urokinase-Type Plasminogen Activator，PLAU)的作用。由於IGFBP3已被報導會阻斷uPA及基質金屬蛋白酶2路徑進而抑制肺癌細胞的轉移能力，在肺癌細胞中降低PLAU的表現可以抑制肌動蛋白骨架的形成，而抑制細胞的轉移及侵害能力，因此我們認為IGFBP3及PLAU可能是HMOX1調控細胞移動能力路徑的下游基因。總合以上結果，我們證明SEMA6A可透過NRF2/HMOX1路徑來減低非小細胞肺癌細胞的移動能力。 | zh_TW |
| dc.description.abstract | Lung cancer is the leading cause of cancer death worldwide and its prevention is a major challenge. Non-small cell lung carcinoma (NSCLC) is the most frequently occurring of lung cancer cell type and accounts for approximately 85 % of lung cancer. Despite recent advances in diagnosis and treatment, the 5-year survival rate of lung cancer is still very poor. As approximately one-half of lung cancers become metastatic and causing in more than 90% of deaths. Therefore, understanding the potential mechanism of lung cancer metastasis may improve the efficacy of cancer treatment. Our previous study indicated that semaphorin 6A (SEMA6A) was down-regulated in lung cancer tissues. Overexpression of SEMA6A caused cell apoptosis, growth inhibition, and decreased cell migration in the lung cancer cell lines. Thus, SEMA6A may play an important role in lung cancer cells and be a potential therapeutic target for lung cancer treatment. In the present study, I further elucidate the mechanism of SEMA6A-regulated migration in H1299 lung cancer cells. First, I analyzed the microarray data from SEMA6A overexpressed H1299 cells. The results showed that heme oxygenase1 (HMOX1), a gene related to cell migration, was up-regulated. Then, we mantipulated the HMOX1 gene in H1299 cells and detected cell migration by transwell assay and wound healing assay. The results revealed that overexpression of HMOX1 reduced the migration ability in the H1299 cells. In consistent, the metastatic ability of H1299 cells increased when HMOX1 was reduced by shRNA. Moreover, reducing of HMOX1 in the SEMA6A-overexpressing H1299 cells recovered the SEMA6A-decreased cell migration ability. In addition, nuclear factor erythroid 2 like 2 (NRF2), an inducer of HMOX1, was up-regulated in the SEMA6A-overexpressing H1299 cells. I further demonstrated that HMOX1 expression was down-regulated in the NRF2 knockdown cells, and attenuated the cell migration ability in SEMA6A-overexpressing cells. On the other hand, reducing of HMOX1 attenuated the up-regulation of IGFBP3 and the down-regulation of PLAU in the SEMA6A-overexpressing cells. Since IGFBP3 and PLAU had been reported to reduce and to induce lung cancer cell metastasis, respectively, this result suggested that IGFBP3 and PLAU might be the downstream genes of HMOX1 in SEMA6A-derived pathway. Taken together, our results provide the first evidence that semaphorin 6A reduces migration of non-small cell lung cancer cells via NRF2/HMOX1 axis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T02:13:05Z (GMT). No. of bitstreams: 1 ntu-106-R04642009-1.pdf: 3157019 bytes, checksum: 12f08fa2db68d04757f0c3b97be183ee (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 致謝 I
中文摘要 II Abstract IV 表目錄 IX 圖目錄 X 第一章、文獻回顧 1 1-1 肺癌 1 1-1-1肺癌的介紹 1 1-1-2肺癌致病原因與機制 2 1-1-3肺癌轉移 5 1-1-4肺癌轉移原因與機制 6 1-2 Semaphroins 8 1-2-1 Semaphroins的介紹 8 1-2-2 Semaphroins調控的訊號路徑 9 1-2-3 Semaphroins蛋白與癌症的研究 11 1-3 HMOX1基因 13 1-3-1 HMOX1基因的介紹 13 1-3-2 HMOX1與癌症的研究 14 第二章、研究動機與架構 16 第三章、實驗材料與方法 17 3-1 培養液配置 (medium Preparation) 17 3-2 細胞培養與繼代 18 3-4 病毒感染(Cell Infection) 21 3-5 分析RNA表現 22 3-6 聚合酶連鎖反應 24 3-7 穿膜試驗（Transwell Assay） 25 3-8 傷口癒合實驗(Wound Healing Assay) 26 3-9 分析蛋白質表現 26 3-10 統計方法 29 第四章、實驗結果 30 4-1 探討Semaphorin 6A對於肺癌細胞遷移能力的影響 30 4-2 探討Semaphorin 6A以哪一部分影響肺癌細胞遷移能力 30 4-3 以微陣列篩選參與SEMA6A調控癌細胞遷移之基因 31 4-4 探討SQSTM1在肺癌細胞中調控遷移能力的影響 32 4-5 探討HMOX1在肺癌細胞中調控遷移能力的影響 33 4-6 探討HMOX1是否參與Semaphorin 6A調控肺癌細胞轉移能力的路徑中 34 4-7 尋找Semaphorin 6A調控HMOX1路徑中間可能的基因 36 4-8 尋找Semaphorin 6A調控HMOX1路徑其下游可能的基因 37 第五章、結論與討論 39 5.1探討HMOX1與肺癌細胞移動能力間的關係 39 5.2 NRF2、GRP78與DDIT3和HMOX1之間的關係 40 5.3 探討NRF2與肺癌移動能力間的關係 41 5.4 探討NRF2/HMOX1路徑對肺癌細胞移動能力之調控 42 5.5 探討SEMA6A調控NRF2/HMOX1可能的機制 43 5.6 探討SEMA6A/NRF2/HMOX1路徑中可能的下游基因，IGFBP3及PLAU，扮演的角色 44 5.7 SEMA6A和EMT markers 46 第六章、未來研究方向 48 參考文獻 73 | |
| dc.language.iso | zh-TW | |
| dc.subject | NRF2 | zh_TW |
| dc.subject | HMOX1 | zh_TW |
| dc.subject | 細胞轉移 | zh_TW |
| dc.subject | Semaphorin 6A | zh_TW |
| dc.subject | 肺癌 | zh_TW |
| dc.subject | lung cancer | en |
| dc.subject | Semaphorin 6A | en |
| dc.subject | HMOX1 | en |
| dc.subject | migration | en |
| dc.subject | NRF2 | en |
| dc.title | Semaphorin 6A透過NRF2/HMOX1降低非小細胞肺癌之轉移能力 | zh_TW |
| dc.title | Semaphorin 6A reduces cell migration through NRF2/HMOX1 in non-small cell lung cancer cells | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 106-1 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 莊曜宇,賴亮全 | |
| dc.subject.keyword | 肺癌,Semaphorin 6A,HMOX1,細胞轉移,NRF2, | zh_TW |
| dc.subject.keyword | lung cancer,Semaphorin 6A,HMOX1,migration,NRF2, | en |
| dc.relation.page | 83 | |
| dc.identifier.doi | 10.6342/NTU201704437 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-12-10 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 生物科技研究所 | zh_TW |
| 顯示於系所單位： | 生物科技研究所 | |
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