Interplay of insulin-like growth factor-II, insulin-like growth factor-I, insulin-like growth factor-I receptor, COX-2, and matrix metalloproteinase-7, play key roles in the early stage of colorectal carcinogenesis.
OBJECTIVE
The aim of this study was to characterize the relationship of insulin-like growth factor (IGF)-II expression with IGF-I, IGF-I receptor (IGF-IR), cyclooxygenase-2 (COX-2), and matrix metalloproteinase (MMP)-7 in early colorectal carcinogenesis.


METHODS
With the semiquantitative reverse transcriptase-PCR, 90 human colorectal tumor tissues (63 adenomas and 27 submucosal pT1 cancers) were analyzed for IGF-II, IGF-IR, IGF-I, COX-2, and MMP-7 expression. Ninety-nine adenoma tissues and 60 pT1 cancer tissues were also analyzed immunohistochemically for IGF-II expression. Loss of imprinting of the IGF-II gene was analyzed. Paired carcinoma and adenoma tissues obtained from a carcinoma in adenoma lesion was analyzed by a cDNA array.


RESULTS
IGF-II mRNA expression was detected in 37.8% of the 90 colorectal tumor tissues. The frequency of IGF-II mRNA expression was significantly higher in pT1 cancer (70.4%) than in adenoma (23.8%). Immunohistochemical IGF-II expression was also more frequently detected in pT1 cancer (58.3%) than in adenoma (25.3%). Loss of imprinting of the IGF-II gene was observed in 15 (44.1%) of the 34 colorectal tumors in which IGF-II was overexpressed. IGF-II expression was positively correlated with the expression of IGF-IR and IGF-I. COX-2 and MMP-7 mRNA expression was detected in 42.2% and 77.8% of the tumor tissues, respectively, and both were positively correlated with IGF-I, IGF-II, and IGF-IR expression. IGF-II was the most differentially expressed gene between carcinoma and adenoma lesions.


CONCLUSIONS
IGF-II, in conjunction with IGF-IR, IGF-I, COX-2, and MMP-7, seems to play a key role in the early stage of colorectal carcinogenesis.
Nosho
Katsuhiko
K
First Department of Internal Medicine, Sapporo Medical University, S.-1, W.-16, Chuo-ku, Sapporo 060-8543, Japan. nosho@sapmed.ac.jp
Yamamoto
Hiroyuki
H
Taniguchi
Hiroaki
H
Adachi
Yasushi
Y
Yoshida
Yukinari
Y
Arimura
Yoshiaki
Y
Endo
Takao
T
Hinoda
Yuji
Y
Imai
Kohzoh
K
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000236:Adenoma / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008565:Membrane Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D017526:Receptor, IGF Type 1; D020783:Matrix Metalloproteinase 7