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研究生:李雅清
研究生(外文):Ya-Ching Li
論文名稱:腫瘤相關胰蛋白酶抑制蛋白在肝細胞癌中的表現:臨床病理學及細胞功能之研究
論文名稱(外文):Expression of tumor associated trypsin inhibitor in hepatocellular carcinoma: Clinicopathological and cell functional studies
指導教授:歐月星許輝吉許輝吉引用關係
指導教授(外文):Yueh-Hsing OuHey-Chi Hsu
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:醫學生物技術研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:81
中文關鍵詞:腫瘤相關胰蛋白酶抑制蛋白基因在肝癌中表現情形
外文關鍵詞:Expression of tumor associated trypsin inhibitor in hepatocellular carcinoma
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肝細胞癌好發於亞洲地區,尤其是中國大陸、香港及台灣,目前治療的預後不佳,診斷方法與敏感度又不夠高,因而肝癌的早期診斷及致病因素的闡明是一重要課題。基於如此,此次實驗是利用基因分示法篩選在肝癌檢體中有過度表現的基因,腫瘤相關胰蛋白酶抑制蛋白 (tumor associated trypsin inhibitor,TATI)基因就是其中之一。TATI是一分泌性蛋白質,可在腸胃道、血液及尿液中發現,雖然TATI在許多腫瘤組織中有增加現象,如卵巢癌、腎臟癌、胰臟癌、大腸直腸癌及肝癌等,但其在腫瘤扮演的角色卻不清楚,有些研究顯示TATI在細胞中的表現會促進DNA的合成,但是TATI對腫瘤而言,其所扮演的角色尚未釐清。
在本篇論文中探討TATI基因在肝細胞癌組織表現情形及細胞內持續過度表現TATI蛋白質的影響:
(A) 在肝臟惡性腫瘤中TATI mRNA 的表現情形,以反轉錄聚合酶連鎖
反應分析224例原發性肝細胞癌 (primary HCC)中154例 (69%)有
過度表現,6例肝芽細胞癌 (hepatoblastoma)中有3例,7例膽管
細胞癌 (cholangiocellular carcinoma)中有2例,6例轉移性結
腸直腸癌 (metastatic colorectal carcinoma,CRC)中有5例被
發現有TATI mRNA過度表現情形,顯示TATI mRNA在多種肝臟的原
發癌及轉移性結腸直腸癌的腫瘤檢體都常見過度表現的情形。
(B) 在臨床病理相關(clinicopathological correlation)分析中,
我們選取224個原發性肝細胞癌,發現TATI mRNA過度表現明顯好
發於女性患者 (84% versus 64%,P值=0.0047),其與血清AFP升
高 (83% versus 54%,P值=0.00001)、TATI mRNA過度表現較常
見於超過5公分的腫瘤 (78% versus 60%,P值=0.011)、有早期
復發 (79% versus 59%,P值=0.0012)及有早期腫瘤轉移現象 (
83% versus 63%,P值=0.032)的病例呈正相關。同時也觀察到在
Ⅲ-Ⅳ分級的腫瘤中 (73% versus 62%,P值=0.068) TATI mRNA
有過度表現的傾向。當肝細胞癌病人有TATI mRNA的過度表現時
存活率較低 (P值<0.002)。
(C) 不論是HeLa細胞呈現穩定表現TATI蛋白質,或是以含有TATI蛋白
質的condtion medium和其他細胞混合培養,都發現TATI蛋白質
對細胞生長速率無明顯的影響。但在3D gel assay中,發現TATI
蛋白質在HeLa細胞株表現時會促進細胞伸出偽足,且細胞伸出偽
足的比例和TATI蛋白質表現量成正比。在半固體瓊脂培養基實
驗 (soft agar)中,發現穩定表現TATI蛋白質的HeLa細胞株可以
在缺乏依附情況下 (anchorage-independent)形成較多且較大的
細胞群落,細胞群落形成的大小及數目和TATI蛋白質表現量成正
比。
(D) 利用細菌大量合成GST-TATI蛋白質,將之作為抗原以製備anti- TATI多株抗體,此抗體可用於西方點墨法及化學免疫組織染色
中。未來應可用於ELISA檢測血清TATI之用。
綜合上述的實驗結果,得知TATI基因在肝細胞癌中有過度表現情形,而TATI基因過度表現和病人血清AFP上升、腫瘤大小、早期復發及早期轉移現象的情況成正相關,且TATI基因過度表現的病人其存活時間較短,因此TATI似可作為腫瘤惡性化及不良預後的指標。在研究TATI蛋白質在細胞階層中的作用時,發現TATI蛋白質會影響細胞侵犯能力及非貼附性生長能力,但其在動物體內的所扮演角色需進一步驗證。
Hepatocellular carcinoma (HCC) is one of the most frequent visceral neoplasms in Asia, especially in Mainland China, Hongkong and Taiwan. The patient often has poor prognosis after treatment, and the low sensitivity in the present diagnosis. Therefore, the early detection and pathogenesis determination were the critical concern. Base on this reason, we have to look for the overexpression gene in HCC by using the differential display method in this study. The tumor associated trypsin inhibitor (TATI) gene was one of them. TATI is a secreted protein found in gastrointestinal tissues, plasma and urine. The TATI are overexpression in many malignant tumor, such as ovarian cancer, kidney cancer, pancreas cancer, colon cancer and liver cancer, some studies show the TATI can promote the DNA synthesis, but the roles of TATI in the tumor tissue is remain unclear.
In this study, we analyze the TATI mRNA expression in HCC and the effect of continuously TATI gene expression in tumor cell:
(A) Using the RT-PCR detection, the overexpression of TATI
mRNA was found in 154 (69%) out of 224 primary
unifocal HCCs, 3 out of 6 hepatoblastomas, 2 out of 7
cholangiocellular carcinomas, 5 out of 6 metastatic
colorectal carcinomas (CRC).
(B) For clinicopathological correlation, the 224 patients
with unifocal primary HCC were selected for analysis.
HCC with TATI mRNA overexpression was more often of
female (84% versus 64% P=0.0047), serum AFP elevation
(83% versus 54%, P=0.00001), tumor size more than 5 cm
(78% versus 60%, P=0.011) and early recurrent (79%
versus 59%, P=0.0012) and early metastasis (83% versus
63%, P=0.032). Moreover, HCC with overexpression of
TATI mRNA in III-IV grade (73% versus 62%, P=0.068)
and had a lower survival (P<0.002).
(C) Neither overexpressed TATI protein in HeLa cells nor
the other cells co-culture with condition medium
contain TATI secreted protein form TATI stable
expression HeLa cells, the proliferation of cells were
no significant. In the 3D gel (type I collagen gel)
assay, the TATI stable expreesion HeLa cells can
promote the pseudopodium formation, and the
pseudopodium formation frequency was correspond to the
TATI protein amount in TATI stable expression HeLa
cells. In soft agar assay, the anchorage-independent
colonies formation capability was also correspond to
the TATI protein amount in TATI stable expression HeLa
cells.
(D) Using the recombinant GST-TATI protein production from
bacteria, we production the polyclone antibody, which
can be used in western blotting and
immunohistochemistry staining. It may use in the ELISA
assay future.
In conclusion, We demonstrated that TATI mRNA was overexpressed in tumor cells and the overexpression in HCC correlated with AFP elevation, tumor size, early recurrent, early metastasis and unfavorable progression. The TATI expression in the HCC could be a potential marker in predicting tumor malignancy and poor prognosis. In cells assay, the TATI could promote the pseudopodium and anchorage-independent colony formation, but the tumorigenesis assay in animal (nude mice) should be further clarification.
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