本研究室先前根據DNA微矩陣資料的探勘(data-mining)與分析，發現STMN1 基因在肝臟腫瘤細胞中有高度表現的情形。進一步在肝臟腫瘤細胞株以及肝臟腫瘤病患之腫瘤組織中檢驗其mRNA及protein的表現量，證實STMN1為一個肝臟腫瘤的標誌。然而，在肝臟腫瘤中STMN1基因的高度表現其分子機制仍然不確定。本研究的主要目的在尋找一些可能在肝臟腫瘤中調控STMN1 mRNA及protein高度表現的因子。利用三個肝癌細胞株：SK-Hep1、Hep-3B與Hep-G2，以及收集之58對病人組織樣本進行分析。由定量即時聚合&#37238;鍊鎖反應與西方點墨法證實了STMN1在其mRNA及protein層面相較於相同病人的正常肝臟組織中均有顯著上升的表現。免疫螢光染色法顯示其在細胞中表現之位置為細胞質。此外本研究也證實了在肝臟腫瘤病患之腫瘤組織中STMN1 protein的表現量確實和其mRNA的表現有高度的正相關[在肝臟腫瘤(HCC)中N=35; r=0.843; p<0.05;在轉移性肝臟腫瘤(Liver metastasis)中N=11; r=0.947; p<0.05)。在46對病患之腫瘤組織中(HCC=35; Metastasis=11)也發現E2F1 protein相較於相同病人的正常肝臟組織也有顯著上升的表現(p<0.05)，同時相對於STMN1蛋白質也有高度正相關(在HCC中N=35; r=0.556; p<0.05; 在Metastasis中N=11; r=0.524; p<0.05)。SK-Hep1及Hep-3B二株細胞的細胞週期實驗中更證實STMN1可能藉由E2F1轉錄因子所調控。另外，在Comparative mapping及染色質免疫沉澱技術也鑑別出STMN1 proximal promoter region上有二個E2F1的結合位置及三個MYC的結合位置(the E box)。經由RNA干擾技術實驗降低SK-Hep1細胞中的E2F1蛋白質表現量，發現細胞中內生性STMN1蛋白質的表現也隨之下降31~36%，進一步支持STMN1的表現是受到E2F1調控。最後，本研究證實在肝臟腫瘤及轉移性肝臟腫瘤中STMN1 protein的高度表現是來自其mRNA的高度表現，而E2F1因子在其中則扮演調控STMN1轉錄之重要角色。

In a preliminary cDNA microarray data-mining, stathmin (STMN1) was identified to be up-regulated in the Hepatocellular carcinomas (HCC). A further screening on HCC cell lines and some tissue specimens at both the mRNA and protein levels, STMN1 was confirmed to be a HCC tumor marker. However, the underlying mechanism that regulates STMN1 up-regulation in HCC is still unknown. The objective of this study was to identify the potential factors that up-regulate STMN1 mRNA and protein levels in HCC. Three HCC cell lines (SK-Hep1, Hep-3B and Hep-G2) and fifty-eight specimens (liver tumor and adjacent nontumor tissues in the same patient) were obtained. Quantitative real-time polymerase chain reaction and western blotting identified up-regulations of STMN1 at both mRNAs and proteins levels in three HCC cell lines and 58 specimens. Immunofluorescence assays further detected its cytoplasmical subcellular localization. Among tumor specimens, the STMN1 protein was significantly correlated with its mRNA expression level (In HCC; N=35; r=0.843; p<0.05; In Metastasis; N=11; r=0.947; p<0.05). In 46 tissue specimens (HCC=35; Metastasis=11), the expression level of E2F1 transcription factor was found to be up-regulated significantly in tumor specimens (p<0.05) and parallel to the STMN1 protein (In HCC; N=35; r=0.556; p<0.05; In Metastasis; N=11; r=0.524; p<0.05). In synchronized SK-Hep1 and Hep-3B cells, it hypothesizes that STMN1 expression is, in part, under the control of E2F1 transcription factors. Moreover, comparative mapping and chromatin immunoprecipitation assay confirmed two E2F1 and three MYC binding sites (the E box) in the STMN1 proximal promoter region. STMN1 proteins were down regulated after the electroporation of shE2F1 in SK-Hep1 cells in 31~36%. In conclusion, the high level of STMN1 protein was resulted from STMN1 mRNA up-regulation and E2F1 might play an important role to transactivate STMN1 gene in HCC and liver metastasis.

中文摘要 I
Abstract II
Abbreviations III
Introduction 1
Materials and methods 17
-Cell lines, tissue samples and plasmids collection 17
-Anti-STMN1 antibody preparation 17
-Transient transfection of expression vector 18
-Quantitative real-time polymerase chain reaction (qPCR) 18
-Western blot analysis 19
-Immunocytochemistry (ICC) 19
-Immunohistochemistry (IHC) 20
-Cell cycle flow cytometry assay 20
-Chromatin Immunoprecipitation (ChIP) assay 21
-Short hairpin RNA interference (shRNAi) 22
-Statistical analysis 22
Tables 23
Results 28
-Analysis of STMN1 mRNA, protein expression and DNA copy numbers in three HCC cell lines 28
-Expression and subcellular localization of STMN1 in three HCC cell lines (SK-Hep1, Hep-3B and Hep-G2) 29
-Analysis of STMN1 mRNA and protein expression in HCC tissue specimens 30
-Clinical evidence relationship between the expression of STMN1 and several transcription factors, RB1, MYC, E2F1 and TP53 in HCC cell lines and specimens 32
-STMN1 expression is cell-cycle-regulated 33
-Identify of canonical E2F1 binding sites and E boxes in STMN1promoter and confirmed E2F1 and MYC proteins bind to STMN1 promoter in vivo 34
-Reduction of E2F1 activity causes decreased STMN1 expression 35
Figures 37
Discussion 51
References 54
Appendix 68

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