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 |
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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 |
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