2017-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/660809摘要：上皮間質轉化(epithelial-mesenchymal transition)，是正常細胞轉化為癌細胞，或是較輕微癌腫轉變為惡性腫瘤的過程。在上皮間質轉化過程中，細胞由原本互相產生緊密連結並有方向性的上皮細胞，轉變為移動能力強的間質細胞型態。經此轉化後，癌腫較容易產生轉移的現象，也就是有較差的預後情形(poor prognosis)。近來有許多文獻提出，癌細胞變得較惡性時，細胞內的代謝過程會有很大的轉變，這種轉變稱為代謝重新編程(metabolic reprogramming)，最引人注目的就是粒線體兩大原料代謝過程的變化，葡萄糖(glucose metabolism)和麩醯胺酸代謝(glutamine metabolism)。學者指出，此兩種代謝轉變可以當作癌腫惡化的指標。在近幾年間也有多篇文獻提出癌細胞的EMT會改變細胞內代謝重新編程，而代謝改變也可能影響癌細胞EMT的過程。我們在前次計畫執行過程中發現，當乳癌細胞內NRF2增加時，除了提高細胞在缺氧狀態下的抗藥性外，細胞外觀有明顯的改變，由原本的圓形變成紡錘狀，並增加移動能力，顯示細胞可能趨向較惡性的狀態。因此，在此計畫中，我們將研究NRF2影響上皮間質轉化與代謝重新編程的機轉，並探討這些轉變與癌腫轉移的關聯。在三年的計畫中，我們的目的為：1.探討NRF2對上皮間質轉換(EMT)與癌細胞轉移(metastasis)之影響2.研究NRF2對乳癌代謝重新編程(metabolic reprogramming)之調整3.了解上皮間質轉換與代謝重新編程之關聯與調節方式4.研究NRF2引致之EMT與代謝轉變對癌腫轉移的調控<br> Abstract: Epithelial-mesenchymal transition (EMT) is a transformation process of a cell from epithelial type with polarity to mesenchymal type with migration ability. During the process, a tumor becomes higher metastatic with poor prognosis.Many references reported that the metabolism process alters in poor prognostic cancers, and this alteration is called “metabolic reprogramming”. The most dramatic metabolic changes are glucose and glutamine metabolisms, which are the two main resources of mitochondria for energy production. Some researchers mentioned that the metabolic changes of these two nutrients can be the markers for poor prognostic tumors. Recently, some references indicated that EMT process changes the metabolism, and metabolism may alter EMT as well.NRF2, the key regulator of antioxidant and detoxified ability, is related to tumor poor prognosis. In the last project, we found that NRF2 can increase the drug resistance under hypoxic microenvironment in breast cancer cells. We also found a significant morphological change in NRF2 overexpression cells, cells became spindle shape and the cell mobility increased a lot. This morphological change and the migration ability increase indicate that cell with higher NRF2 expression level may become poorer prognostic. Therefore, we decide to study the effects and the underlying mechanisms of NRF2 on EMT process and metabolic reprogramming.Proposes of the three-year project are listed below:1. Study the effects of NRF2 on EMT and tumor metastasis.2. Study the regulation of NRF2 on metabolic reprogramming.3. Explore the regulation and the interaction between EMT and metabolic reprogramming.4. Investigate the regulation of NRF2-induced EMT and metabolic changes on tumor metastasis in vivo.NRF2上皮間質轉化癌細胞移行能力代謝重新編程葡萄糖代謝麩醯胺酸代謝癌腫轉移NRF2Epithelial-MesenchymalTransition (EMT)migrationmetabolic reprogrammingglucose metabolismglutamine metabolismtumor metastasis