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Sustained Mutant KIT Activation in the Golgi Complex Is Mediated by PKC-θ in Gastrointestinal Stromal Tumors

 Won Kyu Kim  ;  SeongJu Yun  ;  Cheol Keun Park  ;  Sebastian Bauer  ;  Jiyoon Kim  ;  Min Goo Lee  ;  Hoguen Kim 
 CLINICAL CANCER RESEARCH, Vol.23(3) : 845-856, 2017 
Journal Title
Issue Date
Animals ; Cell Line ; Disease-Free Survival ; Endoplasmic Reticulum/enzymology* ; Enzyme Activation ; Gastrointestinal Neoplasms/enzymology* ; Gastrointestinal Neoplasms/mortality ; Gastrointestinal Neoplasms/pathology ; Gastrointestinal Stromal Tumors/enzymology* ; Gastrointestinal Stromal Tumors/mortality ; Gastrointestinal Stromal Tumors/pathology ; Gene Expression Regulation, Neoplastic ; Golgi Apparatus/enzymology* ; Humans ; Kaplan-Meier Estimate ; Mutation ; Neoplasm Proteins/genetics* ; Neoplasm Proteins/physiology ; Proteasome Endopeptidase Complex/metabolism ; Protein Kinase C-theta/physiology* ; Proteolysis ; Proto-Oncogene Proteins c-kit/genetics* ; Proto-Oncogene Proteins c-kit/metabolism ; RNA Interference ; RNA, Small Interfering/genetics
PURPOSE: Tumorigenesis of gastrointestinal stromal tumors (GIST) is driven by gain-of-function mutations in the KIT gene, which result in overexpression of activated mutant KIT proteins (MT-KIT). However, the mechanism of MT-KIT overexpression is poorly understood.

EXPERIMENTAL DESIGN: By protein expression analysis and immunofluorescent microscopic analysis, we determine the stability and localization of MT-KIT in four GIST cell lines with different mutations and HeLa cells transfected with mutant KIT model vectors. We also used 154 human GIST tissues to analyze the relationship between the expression of PKC-θ and MT-KITs, and correlations between PKC-θ overexpression and clinicopathological parameters.

RESULTS: We report that four different MT-KIT proteins are intrinsically less stable than wild-type KIT due to proteasome-mediated degradation and abnormally localized to the endoplasmic reticulum (ER) or the Golgi complex. By screening a MT-KIT-stabilizing factor, we find that PKC-θ is strongly and exclusively expressed in GISTs and interacts with intracellular MT-KIT to promote its stabilization by increased retention in the Golgi complex. In addition, Western blotting analysis using 50 GIST samples shows strong correlation between PKC-θ and MT-KIT expression (correlation coefficient = 0.682, P < 0.000001). Immunohistochemical analysis using 154 GISTs further demonstrates that PKC-θ overexpression significantly correlates with several clinicopathological parameters such as high tumor grade, frequent recurrence/metastasis, and poor patient survival.

CONCLUSIONS: Our findings suggest that sustained MT-KIT overexpression through PKC-θ-mediated stabilization in the Golgi contributes to GIST progression and provides a rationale for anti-PKC-θ therapy in GISTs. Clin Cancer Res; 23(3); 845-56. ©2016 AACR.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Won Kyu(김원규)
Kim, Ji Yoon(김지윤)
Kim, Hogeun(김호근)
Park, Cheol Keun(박철근) ORCID logo https://orcid.org/0000-0001-7689-0386
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
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