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An unconventional KITENIN/ErbB4-mediated downstream signal of EGF upregulates c-Jun and the invasiveness of colorectal cancer cells

 Jeong A. Bae  ;  Somy Yoon  ;  So-Yeon Park  ;  Jae Hyuk Lee  ;  Jun-Eul Hwang  ;  Hangun Kim  ;  Young-Woo Seo  ;  Yoon Jin Cha  ;  Sung Pil Hong  ;  Hoguen Kim  ;  Ik Joo Chung  ;  Kyung Keun Kim 
 CLINICAL CANCER RESEARCH, Vol.20(15) : 4115-4128, 2014 
Journal Title
Issue Date
Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Apoptosis ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism* ; Blotting, Western ; Carrier Proteins/genetics ; Carrier Proteins/metabolism* ; Cell Proliferation ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology* ; Dishevelled Proteins ; Drug Resistance, Neoplasm/drug effects ; Epidermal Growth Factor/pharmacology ; Fluorescent Antibody Technique ; Gene Expression Regulation, Neoplastic/drug effects* ; Humans ; Immunoenzyme Techniques ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism ; Liver Neoplasms/secondary* ; Membrane Proteins/genetics ; Membrane Proteins/metabolism* ; Neoplasm Invasiveness ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Proto-Oncogene Proteins c-jun/genetics ; Proto-Oncogene Proteins c-jun/metabolism* ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Receptor, Epidermal Growth Factor/genetics ; Receptor, Epidermal Growth Factor/metabolism ; Receptor, ErbB-4/genetics ; Receptor, ErbB-4/metabolism* ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction ; Transcription Factor AP-1/genetics ; Transcription Factor AP-1/metabolism ; Transcriptional Activation ; Tumor Cells, Cultured
PURPOSE: EGF-stimulated signaling via EGF receptor (EGFR) is important in colorectal tumorigenesis and drug targeting. However, anti-EGFR therapy is not effective in a subset of patients with colorectal cancer, suggesting that unidentified EGF-stimulated pathways might play roles in colorectal cancer. Previously, we identified KAI1 C-terminal interacting tetraspanin (KITENIN) as a metastasis-enhancing gene and found it to be highly expressed in sporadic colorectal cancer tissues. We recently found that EGF further increases KITENIN-induced elevated AP-1 activity. Here we attempted to clarify this novel EGF-stimulated molecular pathway and its roles in colorectal cancer.

EXPERIMENTAL DESIGN: We analyzed how EGF modulates the downstream signaling pathway of oncogenic KITENIN in colorectal cancer cells. Biological alterations following EGF treatment were identified in KITENIN-overexpressed colorectal cancer cells with or without alteration of EGFR activity.

RESULTS: We identified the KITENIN/ErbB4-Dvl2-c-Jun axis as a novel downstream signal of EGF that is switched on under elevated KITENIN conditions in an EGFR-independent manner. This unconventional EGF signal upregulates c-Jun and enhances invasion and anchorage-independent growth of colorectal cancer cells. In addition, tumor tissues from metastatic patients with colorectal cancer who showed initial poor responses to cetuximab/chemotherapy expressed higher levels of KITENIN than did responders to therapy.

CONCLUSIONS: Our results highlight the role of an EGFR-independent EGF signal in mediating the invasiveness and tumorigenesis of colorectal cancer cells. This unconventional pathway might be related to the limited clinical efficacy of anti-EGFR agents in a subset of patients with colorectal cancer.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Hogeun(김호근)
Cha, Yoon Jin(차윤진) ORCID logo https://orcid.org/0000-0002-5967-4064
Hong, Sung Pil(홍성필)
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