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

Clin Cancer Res. 2014 Aug 1;20(15):4115-28. doi: 10.1158/1078-0432.CCR-13-2863. Epub 2014 Jun 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • 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, 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

Substances

  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • Carrier Proteins
  • DVL2 protein, human
  • Dishevelled Proteins
  • Membrane Proteins
  • Phosphoproteins
  • Proto-Oncogene Proteins c-jun
  • RNA, Messenger
  • Transcription Factor AP-1
  • VANGL1 protein, human
  • Epidermal Growth Factor
  • EGFR protein, human
  • ERBB4 protein, human
  • ErbB Receptors
  • Receptor, ErbB-4