Stem cell factor-mediated wild-type KIT receptor activation is critical for gastrointestinal stromal tumor cell growth

• Published in: World journal of gastroenterology : WJG Vol. 18; no. 23; pp. 2929 - 2937
• Main Author: Bai, Chen-Guang
• Format: Journal Article
• Language: English
• Published: United States Baishideng Publishing Group Co., Limited 21.06.2012
• Subjects: Adult; Aged; Apoptosis - drug effects; Cell Proliferation - drug effects; Female; Gastrointestinal Neoplasms - genetics; Gastrointestinal Neoplasms - metabolism; Gastrointestinal Neoplasms - pathology; Gastrointestinal Stromal Tumors - genetics; Gastrointestinal Stromal Tumors - metabolism; Gastrointestinal Stromal Tumors - pathology; Genotype; Humans; Male; Middle Aged; Mitotic Index; Mutation; Original; Proto-Oncogene Proteins c-kit - drug effects; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Stem Cell Factor - metabolism; Stem Cell Factor - pharmacology; Tumor Cells, Cultured; 介导; 受体; 干细胞因子; 激活; 细胞生长; 胃肠道; 野生型; Cell growth; Wild-type KIT receptor; In vitro; Gastrointestinal stromal tumor; Stem cell factor
• ISSN: 1007-9327; 2219-2840; 2219-2840
• DOI: 10.3748/wjg.v18.i23.2929

AIM： To clarify the biological role of stem cell factor （SCF）-mediated wild-type KIT receptor activation in gastrointestinal stromal tumor （GIST） growth. METHODS： The co-expression of wild-type KIT receptor and SCF was evaluated in 51 GIST samples using mutation analysis and immunohistochemistry, and the results were correlated with clinicopathological param- eters, including the mitotic count, proliferative index （Ki-67 immunohistochemical staining）, mitotic index （phospho-histone H3 immunohistochemical staining） and apoptotic index （terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling）. Using primary cultured GIST cells, the effect of SCF-mediated wild-type KIT receptor activation was determined by western blotting, methyl thiazolyl tetrazolium （MTT）, and apoptosis assays. RESULTS： We found that wild-type KIT receptor and SCF protein were expressed in 100% and 76.5% of the 51 GIST samples, respectively, and the co-expression of wild-type KIT receptor and SCF was associated with known indicators of poor prognosis, including larger tumor size （P = 0.0118）, higher mitotic count （P = 0.0058）, higher proliferative index （P = 0.0012）, higher mitotic index （P = 0.0282）, lower apoptosis index （P = 0.0484）, and increased National Institutes of Health risk level （P = 0.0012）. We also found that the introduction of exogenous SCF potently increased KIT kinase activity, stimulated cell proliferation （P 〈 0.01） and inhibited apoptosis （P 〈 0.01） induced by serum starvation, while a KIT immunoblocking antibody suppressed proliferation （P = 0.01） and promoted apoptosis （P 〈 0.01） in cultured GIST cells. CONCLUSION： SCF-mediated wild-type KIT receptor activation plays an important role in GIST cell growth. The inhibition of SCF-mediated wild-type KIT receptor activation may prove to be particularly important for GIST therapy.