臺灣博碩士論文加值系統

肝癌是全世界癌症死亡的第二大主因，因為肝癌早期的症狀不明顯，所以不容易在初期就診斷出來，可以診斷出的病患一般已是中末期，腫瘤可能已經侵入淋巴甚至轉移至其他部位，因此肝癌患者通常預後不良；全基因組分子生物學研究將有助於肝癌的診斷。蛋白質磷酸化是調控訊息傳遞最主要的方式之一，目前已有數種蛋白激酶抑製劑改善了癌症患者的存活率。本研究室的宋美儀學姊曾建立DPPHCC資料庫，希望能提供全面性的肝癌磷酸化生物標記資料庫及預測平台。DPPHCC資料庫整合了肝癌相關基因及其參與途徑、磷酸化相關基序及蛋白激酶及蛋白質表達資料，分別建構HCC-611子資料庫、MKA子資料庫及GOCU資料集，建立肝癌生物標記及蛋白質磷酸化的評分系統，進行生物標記之預測。然而此資料庫建構過程出現了一些疏漏，因此本研究基於DPPHCC的架構建立了肝癌磷酸化HCCPM記資料庫dBMHCC，進行資料的更正、擴充與更新，並加入了Drug子資料庫的藥物資訊。dBMHCC包含611個肝癌的顯著基因，234個肝癌相關途徑，17個磷酸化相關基序和它們的255個相應蛋白激酶，5955個肝癌HCCPM記，其中1077個被預測為肝癌的磷酸化生物標記。在評分的前10名當中，MAT2B和ADI1分別調控肝癌發展和C型肝炎病毒感染，而分數最高的PDGFRA，為1種肝癌藥物，5種癌症藥物和4種非癌症藥物的靶標，其中對應的癌症藥物可能可以用於肝癌治療中，作為肝癌新藥。dBMHCC是肝癌磷酸化生物標記的開放資源，提供基因表現、實驗驗證類別和相關藥物資訊，來協助研究人員進行新型診斷、藥物設計等發展肝癌相關研究。

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death globally. The symptoms of liver cancer in the early stages are not obvious, thus it is not easy to diagnose.As patients were diagnosed, it usually reaches the late stage, and the tumor may have also spread to lymph nodes but not to other parts of the body. Therefore, patients with hepatocellular carcinoma usually have a poor prognosis. Genome-wide molecular biology studies may help investigate benefit the biology insight of HCC development. According to the importance of phosphorylation on signal transduction, several protein kinase inhibitors have been developed for HCC treatment to improve survival of HCC patients. Our group had built DPPHCC database to provide a comprehensive HCC phosphorylated biomarker database and prediction platform. DPPHCC incorporated HCC related genes and their related pathway, phosphorylation related motif and its corresponding protein kinase, and protein expression profiles. DPPHCC obtained HCC-611, MKA and GOCU databases, and the evaluation systems for HCC marker and phosphorylation prediction. While we found some bugs in DPPHCC, thus we try to update the databases, debug the system, and incorporate the Drug information. dBMHCC contains 611 HCC significant genes, 234 HCC related pathways, 17 phosphorylation related motifs and their 255 corresponding protein kinases, 5955 HCC biomarkers, 1077 predicted HCC phosphorylated biomarkers (HCCPMs). Among the top 10 HCCPMs predicted by dBMHCC, the methionine adenosyltransferase 2B (MAT2B) and acireductone dioxygenase 1 (ADI1) were involved HCC development and hepatitis C virus infection, respectively. Platelet-derived growth factor receptor alpha (PDGFRA), which has the highest evaluation scores, was identified as the target of 1 HCC drug (Regorafenib), 5 cancer drugs, and 4 non-cancer drugs. The cancer drugs may be investigated the feasibility in HCC treatment. dBMHCC is an open resource for HCC phosphorylated biomarkers, which provides expression profiles, evidence type and drug information to support researchers investigating the HCC development and designing the novel diagnosis and drug.

致謝 i
中文摘要 ii
Abstract iii
Contents iv
List of tables vi
List of Figures vii
1. Introduction 1
2. Related Works 5
2.1 HCC related databases 5
2.1.1 OncoDB.HCC 5
2.1.2 EHCO 5
2.1.3 Liverome 5
2.1.4 dbPHCC 6
2.1.5 DPPHCC 6
2.2 Related databases 6
2.2.1 Prosite 6
2.2.2 UniProt 7
2.2.3 PhosphoSitePlus 8
2.2.4 Gene Ontology 9
2.2.5 Cyclebase 10
2.2.6 KEGG 10
2.2.7 DrugBank 11
3. Materials and Methods 12
3.1 HCC-611 database updating 13
3.2 Motif-kinase association (MKA) database updating 14
3.2.1 PhosMotif database updating 15
3.2.2 SPPKinase database updating 15
3.3 Phosphorylation correlation analysis 16
3.4 HCC marker evaluation 16
3.5 Drug information collection 18
4. Results and Discussion 19
4.1 HCC-611 database 19
4.2 MKA database 20
4.3 HCC marker evaluation 21
4.4 HCC phosphorylated marker (HCCPM) evaluation 26
4.5 Drug information 29
4.6 Web interface 29
5. Concusions and future work 41
5.1 Conclusions 41
5.2 Future Work 41
References 42

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