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標題Title: Heat Shock Protein 90 Overexpression Independently Predicts Inferior Disease-Free Survivalwith Differential Expression of the A and B Isoforms in Gastrointestinal Stromal Tumors
作者Authors: 溫義輝,Chien-Feng Li..等
上傳單位Department: 生物科技系
上傳時間Date: 2009-11-16
上傳者Author: 溫義輝
審核單位Department: 生物科技系
審核老師Teacher: 溫義輝
檔案類型Categories: 論文Thesis
關鍵詞Keyword: heat shock protein 90, survival, gastrointestinal stromal tumors
摘要Abstract: Purpose: Most gastrointestinal stromal tumors harbor a mutated KIT or PDGFRA receptor
tyrosine kinase (RTK). Heat shock protein 90 (Hsp90) is a chaperone mediating the folding and
stabilization of many oncoproteins, including KIT. An Hsp90 inhibitor, 17-AAG, can attenuate KIT
activation and proliferationof gastrointestinal stromal tumor cell lines.We further evaluated Hsp90
immunoexpression and the difference between a and h isoforms in gastrointestinal stromal tumor
specimens.
Experimental Design: Hsp90 immunostainwas assessable in 306ca ses on tissuemicroarrays
of primary gastrointestinal stromal tumors and correlated with various variables and disease-free
survival (DFS). RTK mutation variants, confirmed in 142 cases by sequencing with or without
precedent denaturing high pressure liquid chromatography screening, were dichotomized into
two prognostically different groups. Differential expression of transcript and protein isoforms
was measured by real-time reverse transcription-PCR andWestern blotting in 16a nd 6 cases, respectively.
Results: Hsp90overexpression(55%) significantlycorrelatedwithlarger size,nongastric location,
higher mitotic count and NIHrisk level, Ki-67 overexpression (all P V 0.001), and unfavorable RTK
genotypes (P = 0.020). It strongly portended inferior DFS univariately (P < 0.0001) and remained
independent inmultivariate analysis (P =0.031; risk ratio, 2.44), alongwithhigh-riskcategory,Ki-67
overexpression, and old age. For both mRNA and protein, Hsp90h was more abundant than
Hsp90a,whereas the latterwas significantly higher inhigh-risk cases.
Conclusions: Hsp90 overexpression represents a poor prognosticator that correlates
with several adverse parameters, highlighting its role in disease progression and alternative
therapy for high-risk, imatinib-resistant gastrointestinal stromal tumors. Hsp90a seems more
relevant to the intrinsic aggressiveness of gastrointestinal stromal tumors, albeit less abundant
than Hsp90h.

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