Heat shock protein 90 overexpression independently predicts inferior disease-free survival with differential expression of the α and β isoforms in gastrointestinal stromal tumors

Chien Feng Li, Wen Wei Huang, Jing Mei Wu, Shih Chen Yu, Tsung Hui Hu, Yih Huei Uen, Yu Fang Tian, Ching Nan Lin, David Lu, Fu Min Fang, Hsuan Ying Huang

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 proliferation of gastrointestinal stromal tumor cell lines. We further evaluated Hsp90 immunoexpression and the difference between α and β isoforms in gastrointestinal stromal tumor specimens. Experimental Design: Hsp90 immunostain was assessable in 306cases on tissue microarrays 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 and Western blotting in 16and 6 cases, respectively. Results: Hsp90 over expression (55%) significantly correlated with larger size, nongastric location, higher mitotic count and NIH risk level, Ki-67 over expression (all P ≤ 0.001), and unfavorable RTK genotypes (P = 0.020). It strongly portended inferior DFS univariately (P < 0.0001) and remained independent in multivariate analysis (P = 0.031; risk ratio, 2.44), along with high-riskcategory, Ki-67 overexpression, and old age. For both mRNA and protein, Hsp90h was more abundant than Hsp90α, whereas the latter was significantly higher in high-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. Hsp90α seems more relevant to the intrinsic aggressiveness of gastrointestinal stromal tumors, albeit less abundant than Hsp90β.

Original languageEnglish
Pages (from-to)7822-7831
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number23
DOIs
Publication statusPublished - 2008 Dec 1

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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