title: Elevated Coexpression of KITENIN and the ErbB4 CYT-2 Isoform Promotes the Transition from Colon Adenoma to Carcinoma Following APC loss.
abstract: OBJECTIVE
  The molecular events in the malignant progression of colon adenoma after loss of adenomatous polyposis coli (APC) are not fully understood. KITENIN (KAI1 C-terminal interacting tetraspanin) increases the invasiveness of colorectal cancer cells, and we identified a novel EGFR-independent oncogenic signal of EGF that works under coexpressed KITENIN and ErbB4. Here we tested whether elevated KITENIN and ErbB4 contribute to further progression of intestinal adenoma following APC loss.
  
  
  RESULTS
  The intestinal tissues of villin-KITENIN transgenic mice in which villin-driven KITENIN expression induces increased c-Jun expression exhibit mild epithelial cell proliferation but no epithelial lineage changes compared with those of nontransgenic mice. Among the four ErbB4 isoforms, JM-a/CYT-2 and JM-b/CYT-2 exhibited the highest AP-1 activity when cells coexpressing KITENIN and each isoform were stimulated by EGF. Interestingly, predominant overexpression of the ErB4-CYT-2 mRNA as well as increased EGFR expression were observed in intestinal adenoma of APC(min/+) mice, which makes the microenvironment of activated EGF signaling. When we crossed villin-KITENIN mice with APC(min/+) mice, intestinal tumor tissues in the crossed mice showed the characteristics of early-stage invading adenocarcinoma. In patients with colorectal cancer, ErbB4-CYT-2 mRNA expression was significantly greater in tumor tissues than in normal adjacent tissues, but no significant differences in tumor tissue expression were found between different colorectal cancer stages. Furthermore, the mRNA expression of KITENIN and that of ErbB4-CYT-2 were positively correlated in human colorectal cancer tissue.
  
  
  CONCLUSIONS
  Elevated coexpression of KITENIN and ErbB4-CYT-2 promotes the transition of colon adenoma to adenocarcinoma within an APC loss-associated tumor microenvironment.
authors.affiliation: Medical Research Center for Gene Regulation, Chonnam National University Medical School, Kwangju, Korea.
authors.forename: Jeong A
authors.initials: JA
authors.lastname: Bae
authors.affiliation: Medical Research Center for Gene Regulation, Chonnam National University Medical School, Kwangju, Korea.
authors.forename: Dhong Hyo
authors.initials: DH
authors.lastname: Kho
authors.affiliation: Medical Research Center for Gene Regulation, Chonnam National University Medical School, Kwangju, Korea.
authors.forename: Eun Gene
authors.initials: EG
authors.lastname: Sun
authors.affiliation: Medical Research Center for Gene Regulation, Chonnam National University Medical School, Kwangju, Korea.
authors.forename: Yoo-Seung
authors.initials: YS
authors.lastname: Ko
authors.affiliation: Medical Research Center for Gene Regulation, Chonnam National University Medical School, Kwangju, Korea.
authors.forename: Somy
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Department of Pathology, Chonnam National University Medical School, Kwangju, Korea.
authors.forename: Kyung Hwa
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Medical Research Center for Gene Regulation, Chonnam National University Medical School, Kwangju, Korea.
authors.forename: Kyu Youn
authors.initials: KY
authors.lastname: Ahn
authors.affiliation: Department of Pathology, Chonnam National University Medical School, Kwangju, Korea.
authors.forename: Jae Hyuk
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Gastroenterology-Hepatology, Chonnam National University Medical School, Kwangju, Korea.
authors.forename: Young Eun
authors.initials: YE
authors.lastname: Joo
authors.affiliation: Department of Hematology-Oncology, Chonnam National University Medical School, Kwangju, Korea.
authors.forename: Ik Joo
authors.initials: IJ
authors.lastname: Chung
authors.affiliation: Department of Pathology, The Catholic University of Korea, Seoul, Korea.
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Sunchon National University, Sunchon, Korea.
authors.forename: Hangun
authors.initials: H
authors.lastname: Kim
authors.affiliation: Medical Research Center for Gene Regulation, Chonnam National University Medical School, Kwangju, Korea. kimkk@chonnam.ac.kr.
authors.forename: Kyung Keun
authors.initials: KK
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000235:genetics; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D066247:Receptor, ErbB-4 / Q000096:biosynthesis* / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D020033:Protein Isoforms; C528120:Vangl1 protein, mouse; C026615:villin; D004815:Epidermal Growth Factor; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D048031:JNK Mitogen-Activated Protein Kinases