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研究生:鄭永銘
研究生(外文):Yung-Ming Jeng
論文名稱:IMP3與NuSAP基因在肝細胞癌的表現及其臨床病理和功能研究
論文名稱(外文):Clinicopathological and functional studies of hepatocellular carcinoma overexpressed genesIMP3 and NuSAP
指導教授:許輝吉許輝吉引用關係
指導教授(外文):Hey-Chi Hsu
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:病理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:97
語文別:英文
論文頁數:92
中文關鍵詞:肝細胞癌: IMP3NuSAP侵犯
外文關鍵詞:hepatocellular carcinomaIMP3NuSAPInvasion
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為了闡明肝細胞癌的分子病理機制,我們分析了網路上的微陣列資料庫,找出兩個前人較少研究的基因似胰島素生長因子mRNA結合蛋白3(IMP3)和NuSAP為肝細胞癌過度表現的基因。
IMP3是一個在胚胎組織和多種癌症所表現的RNA結合蛋白。之前的研究發現IMP3和它的同源蛋白牽涉到它們標的RNA的穩定度,轉譯和細胞內分佈。IMP3也被發現為侵犯足形成所必須的,但是它在腫瘤生成和進展的角色仍未為人所知。為了分析IMP3在肝細胞癌的角色,我們以免疫組織化學染色法分析人類肝細胞癌樣本中的蛋白質表現,使用RNA干擾法減少IMP3表現和穩定表現IMP3的細胞株以研究它對腫瘤生長和侵犯的影響,以及以cDNA微陣列分析法分析其分子機轉。我們以免疫組織化學染色法分析IMP3在377個手術切除的單病灶的肝細胞癌的表現(296男性,81女性,年齡分佈從7歲到88歲,平均55.49歲)。IMP3表現在其中255個腫瘤(67.6%)。IMP3蛋白較常表現在腫瘤周邊,和侵犯前緣。比起主要的腫瘤,IMP3較常表現在衛星結節和腫瘤栓子。IMP3的表現和血中高甲胎兒蛋白值(>200 ng/mL, P < 1 x 10-7),大的腫瘤(>5公分,P = 0.006),高的腫瘤級別(P < 1 x 10-7),高的腫瘤期別伴隨血管侵犯和各種程度的肝內轉移(P < 1 x 10-7)呈高度相關。 這些觀察提示IMP3的表現和腫瘤分化不良有關,因此,與高的甲胎兒蛋白值和高腫瘤級別呈正相關。更重要的是,我們的發現指出有IMP3表現的肝細胞癌有生長優勢和侵犯和轉移的潛能,因而造成高腫瘤期別和經常出現肝內轉移。IMP3的表現可以預測早期腫瘤復發(P < 1 x 10-7),並且是不良預後的強的預測因子(P<0.0001)。為了證實和闡明IMP3在肝細胞瘤生長和轉移的功能性角色及其分子機制,我們在肝細胞癌細胞株HA22T和子宮頸腺癌HeLa以RNA干擾法耗盡IMP3,並建立穩定表現IMP3的HEK293 細胞。過度表現IMP3會促進細胞的非貼附性生長能力,和HEK293細胞在裸鼠形成腫瘤的能力。反之,在HeLa細胞耗盡IMP3,會抑制在裸鼠體內的腫瘤生長。在肝細胞癌細胞株HA22T以RNA干擾耗盡IMP3造成細胞移動,侵犯,和經內皮移動能力的下降。微陣列分析發現IMP3的耗盡會造成許多和腫瘤侵犯有關的基因的表現量下降。其中,我們發現在肝細胞癌中,HMGA2和IMP3的表現和IMP3的表現呈高度相關(P =0.0002)。這些結果顯示IMP3 在腫瘤生成和侵犯扮演重要角色,並且是肝細胞癌病人的重要預後因子。
NuSAP一開始被發現是一個微管結合和成束蛋白並且被報導為有絲分裂晚期形成紡鍾體中央重要的蛋白質。在細胞周期進行中調節它的功能的機制仍不清楚。為了闡明NuSAP在肝細胞癌的角色,我們以反轉錄-聚合脢鏈反應分析177個肝細胞癌中NuSAP的表現。我們發現在肝細胞癌過度表現表現NuSAP與高腫瘤級別(P=0.045)和期別(P=0.0023)和不良的五年存活率(P=0.033)成正相關。NuSAP的mRNA和蛋白質表現量在晚G2期到有絲分裂期呈高峰,在細胞分裂後突然下降。使用nocodazole同步化的細胞,我們發現NuSAP在晚G2期到有絲分裂早期被磷酸化,而且此磷酸化對依賴循環子的激脢的抑制劑roscovitine敏感。體外磷酸化試驗證實NuSAP是cdk1/cyclin B1複合體的受質。使用對磷酸化NuSAP具特異性的抗體,我們以免疫螢光染色法發現磷酸化的NuSAP在有絲分裂開始時,出現在核仁。在有絲分裂前期和中期出現在染色體周圍層。在有絲分裂後期,末期和細胞周期間期完全消失。體外微管沉降試驗證實 NuSAP的磷酸化抑制其與微管的結合。我們的結果顯示經由NuSAP的磷酸化,NuSAP經由對微管動力學的影響調節有絲分裂紡鍾體的空間和時間控制。
To elucidate the molecular pathogenesis of hepatocellular carcinoma (HCC), we analyzed the web-based microarray database and identified several previously uncharacterized genes that were overexpressed in HCC. In this study, two of these genes, insulin-like growth factor II mRNA-binding protein 3 (IMP3) and NuSAP, which remained largely unknown for their biological function, particularly in human cancer, were subjected to detailed clinicopathological and functional studies to elucidate their roles in tumor progression of HCC.
IMP3 is an mRNA-binding protein expressed in embryonic tissues and multiple cancers. Studies have shown that IMP3 and its homolog proteins are involved in the stability, translation and subcellular localization of their target RNAs. IMP3 has also been shown to be essential for invadopodia formation, but its roles in the tumor development and progression remain largely unknown. To elucidate the roles of IMP3 in HCC, we first examined its protein expression in human HCC samples by immunohistochemical stain to establish its clinical relevance, and then studied the functional role in the tumor cell growth and invasion of HCC cells by the gene knockdown assay using RNA interference (RNAi) and the overexpression of IMP3 using stable cell lines. Finally the molecular mechanisms of the roles of IMP3 in suppressing tumor growth and invasion by gene silencing and the tumor promotion by gene overexpression were investigated by cDNA microarray analysis. The IMP3 protein expression was examined in the surgically resected unifocal primary tumors of 377 HCC patients (296 men and 81 women) with ages ranging from 7 to 88 years (mean, 55.49 years) by immunohistochemistry. IMP3 was expressed in 255 HCCs (67.6%). In the main tumor mass, IMP3 protein was predominantly expressed in the tumor border and invasive front. IMP3 was more abundant in the satellite nodules and tumor thrombi as compared with the main tumors. These findings suggest that IMP3 is actively involved in the tumor invasion and metastasis. The IMP3 protein expression positivity correlated with high α-fetoprotein (AFP; >200 ng/mL, P < 1 x 10-7), larger tumor size (>5 cm; P = 0.006), high tumor grade (P < 1 x 10-7), and high tumor stage with vascular invasion and various degrees of intrahepatic metastasis (P < 1 x 10-7). These observations suggest that IMP3 expression correlates with poor tumor cell differentiation, and hence is associated with higher AFP expression and high tumor grade. Importantly, our findings indicate that HCCs with IMP3 protein expression possess growth advantage and invasion/metastasis potential, hence higher tumor stage with more frequent intrahepatic metastasis. IMP3 expression predicted early tumor recurrence (P < 1 x 10-7) and was a strong indicator of poor prognosis (P < 0.0001). To verify and elucidate the molecular mechanisms of the functional role of IMP3 in HCC growth and metastasis, we knocked down the expression of IMP3 using the RNA interference (RNAi) in HCC cell line HA22T and cervical adenocarcinoma cell line HeLa. We also established ectopic expression of IMP3 in HEK293 cells with stable transfection of IMP3. Overexpression of IMP3 enhanced anchorage-independent cell growth in soft agar and exhibited oncogenic potential of HEK293 cells in vivo in nude mice. On the other hand, knockdown of IMP3 in HeLa cells inhibited tumor growth in nude mice. Moreover, knockdown of IMP3 in HCC cell line HA22T caused a decrease in cell motility, invasion, and transendothelial migration. Microarray analysis revealed that knockdown of IMP3 was associated with downregulation of multiple genes involved in tumor invasion. Among them, we found the expression of HMGA2 was highly correlated with IMP3 expression in HCC (P =0.0002). Taking together, these results indicate that IMP3 plays important roles in tumor formation and invasion and is a strong prognostic factor for HCC.
NuSAP was originally identified as a microtubule binding and bundling protein and an important protein for central spindle formation in late stages of mitosis. The regulatory mechanism for the function of NuSAP during cell cycle progression is still unclear. To elucidate the role of NuSAP in HCC, we analyzed its expression in 177 HCCs by reverse transcription-polymerase chain reaction. We found overexpression of NuSAP in HCC was associated with high tumor grade (P=0.045), stage (P=0.0023), and worse five-year survival (P=0.033). The mRNA and protein levels of NuSAP peaked at the transition of G2 phase to mitosis and abruptly declined after cell division. Using nocodazole synchronized HeLa cells, we found NuSAP was phosphorylated at the late G2 phase and early mitosis, and the phosphorylation was sensitive to cyclin-dependent kinase inhibitor roscovitine. The in vitro phosphorylation assay confirmed NuSAP was a substrate of cdk1/cyclin B1 complex. By immunofluorescence using a phospho-specific antibody, we found phosphorylated NuSAP was detected at nucleoli at the onset of mitosis, shifted to perichromosomal layer at prophase and metaphase and completely lost at anaphase, telophase, and interphase. Phosphorylation of NuSAP inhibited its binding to microtubules in the in-vitro microtubule sedimentation assay. Our results indicate that phosphorylation of NuSAP regulates the spatiotemporal control of mitotic spindle formation by modulating the dynamics of microtubules.
Abstract in English 3
Abstract in Chinese 5
Abbreviation Table 7
Chapter 1: Introduction 8
Chapter 2: IMP3, an oncofetal RNA-binding protein promotes tumor invasion and predicts poor prognosis in hepatocellular carcinoma 15
Introduction 16
Materials and Methods 19
Results 24
Discussion 28
Tables 34
Figures 40
Chapter 3: NuSAP is a cell cycle-regulated microtubule-binding protein 52
Introduction 53
Materials and Methods 57
Results 61
Discussion 64
Tables 68
Figures 70
References 79
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