瓦式效應(Warburg effect)證實了腫瘤細胞即使在氧氣充足的環境之下，仍會提高糖解作用的效率。根據這個學說，細胞的代謝似乎受到腫瘤的癌化情形所影響，在實驗室之前學長的研究中，當HeLa細胞穩定抑制表現六碳糖激酶I型(Hexokinase I)和檸檬酸合成酶(Citrate synthase)後細胞皆有偏向間質細胞的型態變化，因此本實驗想要探討在子宮頸癌調控表皮細胞間質化(epithelial-mesenchymal transition，EMT)相關的基因表現，像Cdh1的沉默表現、Twist，Snail，和Slug過度表現，藉此模擬腫瘤細胞進行表皮細胞間質化的狀況並且研究其代謝變化。因此本實驗首先在HeLa細胞分別建立穩定過度表現Snail，Twist和Slug的細胞株及穩定沉默Cdh1的細胞株，先觀察這些細胞株的癌化情形，發現雖然在HeLa細胞穩定表現這些表皮細胞間質化的相關蛋白質，在生長方面沒有太明顯的影響，但在細胞爬行及細胞群落的形成能力皆有很明顯的提升。在表皮細胞間質化的標記蛋白(EMT marker)表現中發現Twist和Slug的穩定表現其表皮細胞間質化的標記蛋白大部分也都有跟著表現，但Snail的穩定過度表現卻造成CDH1的表現提升，Cdh1的沉默表現卻沒有太明顯的變化。接著分析這些細胞株的代謝變化，首先在處理低濃度的葡萄糖(0，1mg/ml)的情況之下，發現Cdh1沉默表現的細胞株表現敏感，而過度表現Twist，Snail和Slug的細胞株卻比野生型(wild-type)的HeLa細胞還不敏感，而在葡萄糖攝取能力的實驗裡發現這四株細胞株皆有上升的現象，接著分析糖解作用的相關酵素發現過度表現Twist和Snail會促進六碳糖激酶I型表現量上升六碳糖激酶II型表現量下降，而過度表現Slug的細胞株六碳糖激酶II型表現量上升，有趣的是過度表現Snail及Slug細胞的檸檬酸合成酶的表現量皆有明顯的提升，但CDH1的抑制表現發現糖類代謝相關酵素卻都沒有太大的影響，本研究發現，過度表現表皮細胞間質化相關的轉錄因子(transcription factors)確實會讓細胞的糖類代謝產生變化，但詳細的原因還不得而知，有研究指出，低氧氣濃度所誘導表現的HIF-1會和HIF-1結合形成轉錄因子去改變細胞對糖類的需求及細胞生長的能力，因此未來可以朝著HIF-1的變化來研究是否這三個轉錄因子也調控了類似的途徑。

Most cancer cells were observed to maintain higher glycolytic rates than those of normal tissues, even under oxygen-sufficient conditions, so-called “Warburg effect”. According to this theory, the change in metabolism may be due to the tumorigenesis of cancer cells. According to previous studies in our laboratory, when stable knockdown Hexokinase I or Citrate synthase in HeLa cell altered it’s morphology to a mesenchymal-like phenotype. In this study, we show that, manipulating the expression of EMT markers, such as Cdh1, Twist, Snail, and Slug in cervical cancer altered its tumorigenesis and metabolic changes. To study the expression of EMT in tumorigenesis, we successfully established stable HeLa cell lines either over-expressing Snail, Twist and Slug or silencing Cdh1. After observing various characteristics in these stable cell lines, their abilities for migration and colony formation were founded to increase significantly while growth rate changes were hardly detectable. Moreover, most EMT markers have been founded to express only in over-expressing Twist and Slug stable cells while silencing Cdh1 stable cells exhibited no obvious changes. Stable Snail overexpression cell lines, up-regulated the expression of Cdh1. Then, the stable cell lines were treated with low glucose concentrations (0, 1 mg/ml) for analyzing changes in metabolism, shown that knock-down Cdh1 became more sensitive than the wild-type HeLa cell lines. Conversely, over-expressing Twist , Snail and Slug displayed less sensitivity. All of cell lines have better glucose uptake ability then wild-type HeLa cell lines . Next, as the result of examining activities of key enzymes in glycolysis, Hexokinase I expression increased while Hexokinase II decreased in stables over-expressing Twist and Snail. And Hexokinase II increased in stables over-expressing Slug .Interestingly , Citrate synthase’s expression increased in stables over-expression Snail and Slug cell lines. When Cdh1 was knock-downed, no major effect on the activities of Hexokinase I and II was observed. In these experience, we found that, cell’s glucose metabolism will change when we over-expressed EMT-related transcription factors, but we still don’t know the reason . In previous study, when cells treat in hypoxia situation, cell’s HIF-1 will be induced and bind with HIF-1. Then ,this complex will act as transcription factor to modulate cell’s glucose requirement and cell’s growth rate .Hence , we can take more research in HIF-1 pathway whether these three EMT-related transcription factors involve or not in the future .

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