An Unconventional KITENIN/ErbB4-Mediated Downstream Signal of EGF Upregulates c-Jun and the Invasiveness of Colorectal Cancer Cells

Autor: Somy Yoon, Sung Pil Hong, Ik Joo Chung, So Yeon Park, Jun Eul Hwang, Jeong A Bae, Kyung Keun Kim, Jae Hyuk Lee, Yoon Jin Cha, Hoguen Kim, Hangun Kim, Young Woo Seo
Rok vydání: 2014
Předmět:
Transcriptional Activation
Oncology
Cancer Research
medicine.medical_specialty
Receptor
ErbB-4
Proto-Oncogene Proteins c-jun
Colorectal cancer
Blotting
Western
Dishevelled Proteins
Fluorescent Antibody Technique
Apoptosis
Mouse model of colorectal and intestinal cancer
Real-Time Polymerase Chain Reaction
medicine.disease_cause
Immunoenzyme Techniques
Tetraspanin
Internal medicine
Antineoplastic Combined Chemotherapy Protocols
Biomarkers
Tumor
Tumor Cells
Cultured
Humans
Medicine
Neoplasm Invasiveness
RNA
Messenger
ERBB4
Adaptor Proteins
Signal Transducing
Cell Proliferation
Epidermal Growth Factor
Cetuximab
Reverse Transcriptase Polymerase Chain Reaction
business.industry
Liver Neoplasms
c-jun
Membrane Proteins
Cancer
Phosphoproteins
medicine.disease
ErbB Receptors
Gene Expression Regulation
Neoplastic
Transcription Factor AP-1
Drug Resistance
Neoplasm
Carrier Proteins
Colorectal Neoplasms
business
Carcinogenesis
Signal Transduction
medicine.drug
Zdroj: Clinical Cancer Research. 20:4115-4128
ISSN: 1557-3265
1078-0432
Popis: 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. Clin Cancer Res; 20(15); 4115–28. ©2014 AACR.
Databáze: OpenAIRE
Externí odkaz: