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頭頸癌放射抵抗性相關的預後分子特徵與NDRG1在頭頸癌的分子功能之研究

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目錄指導教授推薦書口試委員會審定書致謝.iii中文摘要.ivABSTRACT.vCONTENTS.viLIST OF FIGURES.viiiLIST OF TABLES.xCHAPTER I BACKGROUND AND RATIONALE.11.1 Introduction.11.2 Study aims.6CHAPTER II PROGNOSTIC SIGNATURE ASSOCIATED WITH RADIORESISTANCE IN HEAD AND NECK CANCER VIA TRANSCRIPTOMIC AND BIOINFORMATIC ANALYSES.72.1 Abs

tract.72.2 Background.82.3 Results.92.3.1 Gene expression profile associated with radioresistance in HNC cells.92.3.2 Core molecular pathways associated with radioresistance in HNC cells.102.3.3 Prognostic significance of the 4 core pathways in HNC patients.112.3.4 Prognostic significance of the pan

el of radioresistant genes in HNC patients.122.3.5 Prognostic signature for the prediction of a worse radiotherapeutic outcome in HNC.122.4 Discussion.14CHAPTER III NDRG1 ACTS AS AN ONCOGENE OR TUMOR SUPPRESSOR WITH THE FUNCTIONAL SWITCHING BY ITS 3R MOTIF IN HEAD AND NECK CANCER.193.1 Abstract.193.

2 Background.203.3 Results.233.3.1 NDRG1 functions mainly in cell growth and motility.233.3.2 NDRG1 inhibits cell growth though arresting cells in S-phase.243.3.3 NDRG1 promotes cell motility via the induction of mesenchymal transition.253.3.4 The 3R motif of NDRG1 differentially regulates cell grow

th and motility.253.3.5 The 3R motif of NDRG1 is an essential domain for nuclear translocation.263.3.6 Phosphorylation of NDRG1 at the 3R motif is critical for nuclear translocation and cellular function.283.3.7 Overexpression of NDRG1 in cancers is associated with poor prognosis in patients.313.4 D

iscussion.32CHAPTER IV MATERIALS AND METHODS.39CHAPTER V CONCLUSION.48REFERENCES.50FIGURES.70TABLES.95LIST OF FIGURESFig. 2-1 Verification of the radioresistant phenotype of radioresistant sublines.70Fig. 2-2 Hierarchical clustering analysis of the gene expression profiles among the three HNC cell l

ines and their radioresistant (RR) sublines.71Fig. 2-3 Bioinformatics analysis of the functional pathway contributing to radioresistance in HNC cells.72Fig. 2-4 Prognostic significance of the 4 core functional pathways.73Fig. 2-5 Differential expression of 11 selected genes between low- and high-ris

k groups of HNC patients.74Fig. 2-6 Prognostic significance of the combined 7 RR molecules (IGF1R, LAMC2, ITGA6, ITGB1, ITGB4, LAMA3 and IL6) in HNC patients.75Fig. 2-7 Prognostic significance of the 4 key molecules (IGF1R, LAMC2, ITGB1 and IL-6) in HNC patients receiving radiotherapy.76Fig. 2-8 Dif

ferential expressions of 4 marker proteins (IFG1R, LAMC2, ITGB1, and IL6) between HNC cell lines and their radioresistant sublines.77Fig. 2-9 Prognostic effectiveness of the combined 4 markers in HNC patients receiving radiotherapy.78Fig. 3-1 Global survey of molecular mechanisms reveals NDRG1 funct

ions mainly in the regulations of cell growth and motility.79Fig. 3-2 NDRG1 suppressed cell growth by arresting cells at S-phase.80Fig. 3-3 NDRG1 promoted cell motility via EMT mechanism.82Fig. 3-4 NDRG1-3R motif has minimal effect on cell growth.84Fig. 3-5 NDRG1-3R motif is critical for cellular mo

tility.86Fig. 3-6 NDRG1-3R motif is essential for molecular translocation into nucleus.88Fig. 3-7 Phosphorylation of NDRG1 by GSK3b is critical for nuclear translocation and cell motility.90Fig. 3-8 High level of NDRG1 is significantly associated with poor survival in HNC patients.92Fig. 3-9 High le

vel of NDRG1 is significantly associated with low risk in patients with some types of cancers.93Fig. 3-10 Proposed mechanism for the molecular effect of NDRG1 in HNC.94 LIST OF TABLESTable 2-1 Top 100 up-regulated genes associated with radioresistance in HNC cells.95Table 2-2 Top 50 down-regulated g

enes associated with radioresistance in HNC cells.99Table 2-3 List of up-regulated genes enriched in the four core molecular pathways.101Table 2-4 Prognostic significance of the 16 selected genes in the HNC patients.102Table 2-5 Correlative expressions of the 7 molecules in HNC patients receiving ra

diotherapy.103Table 3-1 Top 50 up-regulated and top 50 down-regulated genes in NDRG1 over-expressing OECM1 cells.104Table 3-2 High level of NDRG1 is significantly associated with poor survival in patients with the majority types of cancer.107