title: An unconventional KITENIN/ErbB4-mediated downstream signal of EGF upregulates c-Jun and the invasiveness of colorectal cancer cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Medical Research Center for Gene Regulation and Center for Creative Biomedical Scientists; Departments of.
authors.forename: Jeong A
authors.initials: JA
authors.lastname: Bae
authors.affiliation: Medical Research Center for Gene Regulation and Center for Creative Biomedical Scientists; Departments of.
authors.forename: Somy
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Medical Research Center for Gene Regulation and Center for Creative Biomedical Scientists; Departments of.
authors.forename: So-Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: Pathology and.
authors.forename: Jae Hyuk
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Hematology-Oncology, Chonnam National University Medical School;
authors.forename: Jun-Eul
authors.initials: JE
authors.lastname: Hwang
authors.affiliation: College of Pharmacy, Sunchon National University;
authors.forename: Hangun
authors.initials: H
authors.lastname: Kim
authors.affiliation: Korea Basic Science Institute, Kwangju Center; Departments of.
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Seo
authors.affiliation: Pathology and.
authors.forename: Yoon Jin
authors.initials: YJ
authors.lastname: Cha
authors.affiliation: Internal Medicine, Yonsei University College of Medicine, South Korea.
authors.forename: Sung Pil
authors.initials: SP
authors.lastname: Hong
authors.affiliation: Pathology and.
authors.forename: Hoguen
authors.initials: H
authors.lastname: Kim
authors.affiliation: Hematology-Oncology, Chonnam National University Medical School;
authors.forename: Ik Joo
authors.initials: IJ
authors.lastname: Chung
authors.affiliation: Medical Research Center for Gene Regulation and Center for Creative Biomedical Scientists; Departments of kimkk@chonnam.ac.kr.
authors.forename: Kyung Keun
authors.initials: KK
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000072261:Dishevelled Proteins; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D066247:Receptor, ErbB-4 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; C488287:VANGL1 protein, human; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4