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Study on Expression of Human Serine Protease Inhibitor HAI-1

Author: ZengLei
Tutor: CaoJiang
School: Zhejiang University
Course: Oncology
Keywords: HAI-1 SNC19/matriptase Gastrointestinal tumors Quantitative PCR Tumor metastasis Protein expression
CLC: R730.2
Type: Master's thesis
Year: 2004
Downloads: 95
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Abstract

Tumorigenesis and progression is duo to a series of sequential interrelated events, in which genes play an important role. Cancer is a genetic disease. Abnormalities in genes’ structures and expression that control cellular proliferation, differentiation lead to the unrestrained growth and anaplasia that characterizes the malignant cell. Nowadays more and more molecular events involved in tumorigenesis have been reported, such as activation of oncogenes, inactivation of tumor suppressors, activation of the cell signaling pathway, defects in cell cycle and apoptotic pathways, and so on. The binding of hepatocyte growth factor/scatter factor (HGF/SF) to its Met receptor results in the activation of the intracellular tyrosine kinase catalytic domain. The recruitment and phosphorylation of specific cytoplasmic proteins by the activated receptor then trigger a series of biochemical events generally leading to cell division. Thus HGF/SF acts as a mitogen, a motogen, and a morphogen for cells expressing Met. HGF/SF and Met play important roles in the invasive growth of tumor cells, which is a hallmark of malignant tumors.Hepatocyte growth factor activator inhibitor type 1 (HA1-1) is a Kunitz-type serine protease inhibitor which was initially purified from the conditioned medium of a human MKN45 stomach carcinoma cell line in 1997. HA1-1 can specifically inhibit serine protease hepatocyte growth factor activator (HGFA) and the newly found SNC/matriptase, which are the activators of HGF/SF. To generate biologically active HGF/SF, the conversion of an inactive single-chain precursor form to a two-chain heterodimeric active form is necessary; and this activation step is a critical limiting step in the HGF/SF-induced signaling pathway. Except for activating HGF/SF, SNC19/matriptase can also degrade extracellular matrix (ECM), and activate urokinase-type plasminbgen activator (uPA). Itcontributes to cellular motility and epithelial migration. Though it was supposed that HAI-1 and SNC19/matriptase may involve in tumorigenesis, progression and metastasis according to their expression in colon cancer and ovarian cancer, the data is not enough. More data is needed to draw a conclusion.HAI-1 has two specific domains, Kunitz I and KunitzII, which can both inhibit serine protease such as HGFA, SNC19/matriptase, plasmin, trypsin. Two Kunitz domains have different inhibitory activity upon different substrates and they may have different function. It may interfere with the binding of HAI-1 to its substrates while the conformation changes in HAI-1. Moreover, whether HAI-1 has different substrates which may involve in tumorigenesis, progression and metastasis, and their relationship is still unknown.The aim of this study is to provide the expression profile of HAI-1 and SNC19/matriptase in normal and malignant tissues of gastrointestinal tract at mRNA level for further study on their correlations with tumor progression and metastasis. We also subcloned five HAI-1 cDNA fragments encoding different domains into expression vector and induced their expression. The protein was purified for further protein interaction research.1. The expression of HAI-1 and SNC19/matriptase in normal and malignant tissues of gastrointestinal tractThe mRNA expression of HAI-1 and SNC19/matriptase in normal and malignant tissues of gastrointestinal tract was detected by realtime fluorescent quantitative RT-PCR technique using glyceraldehydes-3-phophate dehydrogenase(GAPDH) as internal standard, and was evaluated for their correlations with clinicopathological parameters such as stage , lymph node metastasis and histological differentiation.The expressions of HAI-1 and SNC19/matriptase in gastric cancer tissues were markedly lower than those in their adjacent normal tissues(Z=-3.280, .P=0.006; Z=-4.651, P=0.000); while HAI-1 :SNC19/matriptase ratio showed no significant difference between normal and malignant gastric tissuest (p0.05). Analysis of clinicopathological parameters demonstrated decreased expression of HAI-1 and HAI-l:SNC19/mat

Study on Expression of Human Serine Protease Inhibitor HAI-1

Abstract

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