Title

第二型肝細胞生長因子活化抑制者在非小型肺癌細胞上皮-間質轉化扮演的角色

Translated Titles

The role of hepatocyte growth factor activator inhibitor type 2 in epithelial-mesenchymal transition of non-small cell lung carcinoma cells

DOI

10.6342/NTU.2010.01480

Authors

施瀚博

Key Words

第二型肝細胞生長因子活化抑制者 ; 上皮-間質轉化 ; 肺癌 ; Ecadherin Slug ; Beta-catenin ; MMP-9 ; HAI-2 EMT ; lung cancer ; E-cadherin Slug ; Beta-catenin ; MMP-9

PublicationName

臺灣大學生物化學暨分子生物學研究所學位論文

Volume or Term/Year and Month of Publication

2010年

Academic Degree Category

碩士

Advisor

李明學

Content Language

英文

Chinese Abstract

在全世界因癌症所造成的死亡中,肺癌占了最大的部分。肺癌可分為兩種組織型態,包括非小型細胞肺癌(約佔所有肺癌的百分之八十五至九十)以及小型細胞肺癌(約佔所有肺癌中的百分之十至十五)。非小型細胞肺癌普遍在肺癌後期才被診斷出,且伴隨著很差的預後情況。一般來說,蛋白酶失調與非小型細胞肺癌演進過程有相當強的關聯性,尤其是在細胞移動與侵襲的過程。第二型肝細胞生長因子活化抑制者 (HAI-2)是一個最近被鑑定為廣泛性絲胺酸蛋白脢抑制者,被認為可以有效地降低神經膠質瘤(glioma cancer)以及胃癌(gastric cancer)的產生與惡化。在我們先前的研究中指出,隨著非小型細胞肺癌移動侵襲能力的增強,HAI-2基因的表現就愈低,同時伴隨著細胞的型態發生改變。在高度惡化的非小型細胞肺癌中,研究指出癌細胞可透過細胞上皮-間質轉化(epithelial-mesenchymal transition, EMT)的過程,改變細胞型態而提高了細胞移動能力。為了更進一步探討HAI-2在非小型細胞肺癌上皮-間質轉化演進過程所扮演的角色,我們使用了一套由台大醫學院楊泮池院長建構出可模擬非小型細胞肺癌惡化轉移的細胞模式進行研究,包括具低侵略性的CL1-0細胞以及高侵略性的CL1-5細胞。我們發現,當在CL1-5細胞中過量表現HAI-2時,上皮蛋白E-cadherin會隨之增加,另一方面,其他間質蛋白(vimentin, fibronectin, beta-catenin, N-cadherin)表現量則有減低的情形。同時,EMT的演進過程可以受到一些轉錄因子(Snail, Slug, Twist, SIP1)所調控,所以我們想更進一步了解HAI-2對於這些轉錄因子有何影響。我們結果顯示,在CL1-5細胞中過量表現HAI-2時,只有Slug的表現量有受到顯著的改變,其他轉錄因子並無發生太大的變化。此外,HAI-2可以透過降低Erk1/2, Akt, beta-catenin, MMP-9以及EGFR來調控非小型細胞肺癌MET的演進過程。進一步地,我們發現重組蛋白HAI-2可以有效抑制地非小型細胞肺癌的移動與侵襲。這些研究顯示HAI-2可以成為在癌症治療上的潛力胜肽藥物的候選者。綜合以上,我們的結果證實肺癌細胞惡化過程,藉由降低HAI-2的表現,參與肺癌細胞EMT的演進。HAI-2表現則可以透過調控EGFR, Akt, Erk1/2, beta-catenin, Slug, E-cadherin以及MMP-9協助MET的轉化過程。

English Abstract

Lung cancer is the leading cause of cancer mortality in the worldwide and Taiwan. It is categorized into two histological groups including non-small cell lung cancer (NSCLC, about 85-90% of all lung cancers) and the small cell lung cancer (SCLC, about 10-15%). NSCLC is frequently diagnosed at an advanced stage with poor prognosis. Dysregulation of proteolysis has been strongly implicated in the progression of NSCLC, particularly in cancer cell invasion and metastasis. Hepatocyte growth factor activator inhibitor type 2 (HAI-2) is a newly identified serine protease inhibitor which has been shown to be down-regulated in advanced human glioma and gastric cancer. In the previous study, our data showed that the gene expression level of HAI-2 was correlated with epithelial cell morphology and inversely associated with invasive and migratory capacities of NSCLC cells. Since in advanced NSCLC, epithelial-mesenchymal transition (EMT) usually occurs to alter epithelial cells to mesenchymal cells with high motility, we further explored if HAI-2 was involved in the EMT progression of NSCLC, by using a NSLSC progression model including lowly invasive CL1-0 cells and highly invasive CL1-5 cells, established by Dean Yang. Our data showed that ectopic expression of HAI-2 in CL1-5 cells up-regulated an epithelial protein, E-cadherin and down-regulated several mesenchymal proteins, such as vimentin, fibronectin, beta-catenin and N-cadherin. Since the modulation of EMT has been proposed to be regulated by EMT-inducing transcription factors, e.g., Snail, Slug, Twist and SIP1, we further examined the effect of HAI-2 on Snail, Slug, Twist and SIP1 expression. Our results showed that a decrease of HAI-2 expression in CL1-5 cells had a significant effect on Slug expression rather than other EMT-inducing transcription factors. Moreover, HAI-2 expression promoted the MET of NSCLC cells, by down regulation of Erk1/2, Akt, beta-catenin, MMP-9 and EGFR. Moreover, we found that recombinant HAI-2 proteins ably inhibited NSCLC cell migration and invasion. These data suggested that HAI-2 may be a potential peptide drug for cancer therapy. The results taken together indicated that HAI-2 was involved in modulating the mesenchymal-epithelial transition of NSCLC cells, at least in part via down-regulating EGFR, Akt, Erk1/2, beta-catenin, Slug and MMP-9.

Topic Category 醫藥衛生 > 基礎醫學
醫學院 > 生物化學暨分子生物學研究所
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