Original Article
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jun 21, 2012; 18(23): 2929-2937
Published online Jun 21, 2012. doi: 10.3748/wjg.v18.i23.2929
Stem cell factor-mediated wild-type KIT receptor activation is critical for gastrointestinal stromal tumor cell growth
Chen-Guang Bai, Xiao-Wei Hou, Feng Wang, Cen Qiu, Yan Zhu, Ling Huang, Jing Zhao, Jing-Jing Xu, Da-Lie Ma
Chen-Guang Bai, Xiao-Wei Hou, Cen Qiu, Yan Zhu, Da-Lie Ma, Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
Feng Wang, Institute of Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
Ling Huang, Jing Zhao, Jing-Jing Xu, Laboratory of Molecular Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
Author contributions: Bai CG, Hou XW and Wang F contributed equally to this work; Bai CG and Ma DL designed the research; Bai CG, Hou XW, Wang F, Qiu C, Zhu Y, Huang L, Zhao J and Xu JJ performed the research; Bai CG, Hou XW and Ma DL analyzed the data; Bai CG, Hou XW and Wang F wrote the paper; Ma DL revised the manuscript.
Supported by The National Natural Science Foundation of China, No.30700809 and No.30972876
Correspondence to: Da-Lie Ma, Professor, Department of Pathology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China. madalie@126.com
Telephone: +86-21-81873692 Fax: +86-21-81873690
Received: October 17, 2011
Revised: February 27, 2012
Accepted: March 19, 2012
Published online: June 21, 2012
Abstract

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 parameters, 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.

Keywords: Gastrointestinal stromal tumor; Stem cell factor; Wild-type KIT receptor; Cell growth; In vitro