Clinicopathological significance of expression of p-c-Jun, TCF4 and beta-Catenin in colorectal tumors.
BACKGROUND
A recent study has shown that phosphorylated c-Jun (p-c-Jun) interacts with TCF4 to form a complex that cooperatively enhances their transcriptional activity in the presence of beta-Catenin, and that their interaction is critical for mouse intestinal tumorigenesis. To determine the significance of these three proteins in human colorectal tumors, we analyzed their nuclear expression by immunohistochemistry.


METHODS
we analyzed their nuclear expression by immunohistochemistry using paraffin-embedded specimens of 68 resected colorectal tumors, which consisted of 19 adenomas, 14 high-grade intraepithelial neoplasia (HGINs) and 35 adenocarcinomas. We also analyzed the expression of MMP7, which has functional AP-1 and TCF binding sites in its promoter.


RESULTS
Expression of p-c-Jun, TCF4 and beta-Catenin were significantly higher in adenomas than in the adjacent normal epithelia. Expression of p-c-Jun and beta-Catenin in HGINs and adenocarcinomas were also significantly higher than in the adjacent normal epithelia. p-c-Jun expression, but not TCF4 and beta-Catenin, was higher in adenomas and HGINs than in adenocarcinomas, in which p-c-Jun expression was negatively correlated with pT stage progression. Furthermore, significant correlations of expression were observed between p-c-Jun and TCF4 (r = 0.25, p = 0.04), TCF4 and beta-Catenin (r = 0.30, p = 0.01), p-c-Jun and MMP7 (r = 0.26, p = 0.03), and TCF4 and MMP7 (r = 0.39, p = 0.0008), respectively.


CONCLUSIONS
These results suggest that nuclear expression of p-c-Jun, TCF4 and beta-Catenin have important roles in human colorectal tumor development and that p-c-Jun may play a pivotal role in the earlier stages of tumor development.
Takeda
Kayoko
K
Department of Medical Oncology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan. kayoko-t@med.hokudai.ac.jp
Kinoshita
Ichiro
I
Shimizu
Yasushi
Y
Ohba
Yusuke
Y
Itoh
Tomoo
T
Matsuno
Yoshihiro
Y
Shichinohe
Toshiaki
T
Dosaka-Akita
Hirotoshi
H
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000073940:Transcription Factor 4; D018808:Transcription Factor AP-1 / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D051176:beta Catenin; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7