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標題: | 探討LCRMP-1及ID4蛋白質在惡性肺癌中之調控機制 Exploring the Role of LCRMP-1 and ID4 in Malignant Lung Cancer |
作者: | Yuan-Ling Hsu 許元玲 |
指導教授: | 潘思樺(Szu-Hua Pan) |
關鍵字: | 肺腺癌,血管新生,血管擬態,轉移,ID4,LCRMP-1, lung adenocarcinoma,angiogenesis,vasculogenic mimicry,metastasis,ID4,LCRMP-1, |
出版年 : | 2020 |
學位: | 博士 |
摘要: | 癌症是一複雜的過程,其包含了腫瘤細胞的增生、腫瘤新生血管的形成以及腫瘤細胞的轉移等步驟。腫瘤可藉由周邊血管的形成而獲得血中的氧氣及養分,也因此促使了腫瘤的生長以及轉移的發生。由於新生血管對於癌症進程的重要性,科學家們對於腫瘤新生血管的形成進行了許多研究。至今,主要被探討的腫瘤新生血管形成作用可區分為兩類,其一為血管新生,其二為血管擬態。血管新生意即所新生的血管源自於內皮細胞;血管擬態則指癌細胞自身可排列為類血管構造,此兩種血管生成作用皆提供了癌細胞進行轉移的通路。早期,實驗室團隊利用cDNA微陣列晶片對肺腺癌進行研究,發現ID4和LCRMP-1的表現量與癌細胞的侵襲能力有所關聯。然而,兩者在肺癌惡化的進程中所扮演的功能性角色以及所調控的分子機制仍然存在著許多未知值得我們詳細探討。 我們在早期研究中發現ID4是一個會抑制癌細胞移動及侵襲等轉移能力的基因,然而對於其分子調控機制及其在臨床病人上的真實表現情況未進行詳細的探討。在本研究計畫中,為了進一步釐清ID4之於癌轉移分子調控機制的影響,我們再次利用cDNA晶片進行分析,確認了ID4最主要調控的訊息路徑包含了上皮細胞間質轉換作用調控路徑,並發現ID4可透過與SLUG蛋白質結合而促進E-cadherin的表現,達成間質細胞上皮轉換作用而抑制癌轉移。除此之外,在利用臨床資料庫進行分析後,證實ID4表現量與病人存活率呈現負相關,此論述支持ID4可作為一判定肺腺癌病人病程的癌症指標。 另一方面,本實驗團隊在2009年時已證實LCRMP-1扮演著提升侵襲能力的角色,其透過與肌動蛋白核化骨架蛋白WAVE-1的結合增加細胞絲狀偽足的形成,進而促使肺腺癌病人病程惡化。在本研究中,我們發現 LCRMP-1除了刺激癌細胞的侵襲轉移能力外,也與肺癌組織內的血管密度具有正相關的關聯性。進一步地,我們在本研究中揭示了腫瘤細胞中LCRMP-1可作為轉錄作用的協同活化者調控SERPINE1等血管新生因子的分泌而刺激血管新生作用,誘使內皮細胞形成新的微血管;除此之外,表現LCRMP-1的腫瘤細胞也可透過執行內皮細胞轉換作用形成類血管。 綜合上述,本研究的發現對於釐清肺腺癌中與癌症惡化相關之基因所扮演的角色有所助力,並使其能作為未來開發新型抗癌藥物的標的物或是監測癌症病程的診斷指標。 Cancer malignancy is a complex process including tumor neo-vascularization and metastasis. Tumors can rapidly grow and even occur metastasis with neo-vessels to supply the nutrients and oxygens. Till now, two types of blood vessel formation are explored, one is angiogenesis and the other is called vasculogenic mimicry. The former indicates that neo-blood vessels are indirectly formed by endothelial cells; and the latter showed that cancer cells, other than endothelial cells, can directly form blood vessels by itself. Both phenotypes of micro-vessels in tumor arrange the roads that cancer cells can metastasize to distant organs. Previously, our research team discovered that the expressions of inhibitor of DNA binding protein 4 (ID4) and long form collapsin response mediator protein 1 (LCRMP-1) were related to cell invasiveness in lung adenocarcinoma (LADC) cells by cDNA microarray screening. However, the functional roles and their mechanisms of regulation in lung cancer malignancy including vascularization and metastasis remain unclear. Recently, we have displayed ID4 as a new metastasis-related gene which attenuated migration and invasion. However, we did not clarify the regulatory mechanism and the effects of clinical outcome in LADC patients at that time. In order to recognize the regulatory of mechanism in detail, we used cDNA microarray analysis, and presented epithelial-mesenchymal transition (EMT) pathway was the major pathway which ID4 regulated. Moreover, we found that ID4 can promote E-cadherin expression through the binding of SLUG, cause the occurrence of mesenchymal-epithelial transition (MET), and inhibit cancer metastasis. Additionally, we used the clinical database to display that the negative correlation between ID4-expressing level and the survival in LADC patients. The facts supported that ID4 might play as a diagnostic marker in LADC. On the other hand, our laboratory has demonstrated LCRMP-1 is an invasive enhancer, which promoted lung cancer malignancy by increasing the formation of filopodia through binding to the actin nucleation scaffold protein, WAVE-1 in 2009. In this study, we found LCRMP-1 not only promoted cancer metastasis but also had a positive correlation with blood vessel densities in lung tumor tissues. According to the finding, we hypothesized LCRMP-1 may play as an enhancer in tumor vascularization. Moreover, we illustrated that LCRMP-1 played as a transcriptional co-activator in tumor cells. The expression of LCRMP-1 could manipulate the secretion of angiogenic factors such as SERPINE1 to induce endothelial cells forming new micro-vessels, or form mimic neo-blood vessels via endothelial-like cell transformation. In the conclusion, we hope our findings can help us more understanding the role of malignant-related genes in LADC, and to develop the new anticancer therapies or diagnosis markers in the near future. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/77031 |
DOI: | 10.6342/NTU202001685 |
全文授權: | 未授權 |
顯示於系所單位: | 基因體暨蛋白體醫學研究所 |
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