肝細胞代謝異常與癌化之標靶酵素搜尋與分析

細胞發生癌化並非由單一原因引起，其代謝網路非常複雜，近年來癌症治療的方法日新月異，標靶治療對於癌症的治療更是重要突破，標靶藥物就好比導彈，能辨識出腫瘤細胞表面的特定標示或特定的代謝機制，首先必須選好特定的癌細胞做為目標，再利用專一性的藥物針對癌細胞做攻擊而不傷害正常細胞，因此對於如何尋找適合的腫瘤標把變成為目前的研究重點。本研究利用人類肝細胞代謝網路模型Recon2 liver model，進行窮舉法找出每個酵素可調控的部分及結果，與Warburg effect假說及KO(miR122a-/- mouse)、Human Case1、Human Case2等實驗數據做類似率的比較，再進行模擬突變通量均衡分析方法(Mutant Flux balance analysis, MFBA)的計算，分析正常肝細胞與突變肝細胞在穩態下通量分佈，最後我們找到了16個candidates(13 enzymes + 3 exchange reactions)，包括EC 2.7.1.40 (Pyruvate kinase)、EC 1.13.11.6 (3-hydroxyanthranilate 3,4-dioxygenase)、EC 3.5.1.3 (Omega-amidase)等，在產生肝癌過程中可能扮演重要的角色，在其他文獻也有被提及與肝癌或其他癌症相關，之後也能將其他基因或酵素作多種合併，提供可能的肝癌標把做為動物實驗參考，進而做為未來臨床實驗方向。

關鍵字

肝；肝癌；沃柏格效應； Recon2 肝細胞模型；癌症標靶；標靶治療

並列摘要

The cancerization of cells is not caused by a single reason. It involves the complex metabolism. In recent years, the therapy of cancer improves every day. Targeted therapy is a significant development for the treatment of cancer. The drug targets are like missiles, they are able to identify a specific tumor cell type or specific metabolism. First, we have to select a specific cancer cell as the goal, and utilize the drugs to attack specific cancer cell without harming normal cells. Therefore, how to find a suitable target of cancer is currently research emphasis. First, we chose the metabolic network model of human liver cells, Recon2 liver model, as our simulation model. Then, we used enumeration analysis to find out the results that each part of enzymes can be regulated. Finally, we compared our results with the Warburg effect hypothesis and the experimental data of KO(miR122a-/-mouse), Human Case1 and Human Case2. Furthermore, we carried out on an analysis, mutant flux balance analysis (MFBA), to get the distribution of normal liver cells and mutant liver cells in the steady state. Finally, we found out 16 candidates(13 enzymes + 3 exchange reactions) including EC 2.7.1.40 (Pyruvate kinase), EC 1.13.11.6 (3-hydroxyanthranilate 3,4-dioxygenase), EC 3.5.1.3 (Omega-amidase), and so on which with higher similarity to Warburg effect hypothesis and the experimental data. Some of these enzymes are consistent with previous literatures and had been mentioned that are correlated to liver cancer or other cancers. As for those enzymes, that had not been mentioned in the literatures will be able to make various combination with other genes or enzymes, and be valuable clinical trials direction as references in the future. Providing the possible target which may play a crucial factor in hepatocellular carcinoma progression.

並列關鍵字

Liver ； Hepatocellular carcinoma ； Warburg effect ； Recon2 liver model ； Cancer target ； Targeted therapy

參考文獻

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肝細胞代謝異常與癌化之標靶酵素搜尋與分析

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