Overexpression of poly(ADP-ribose) polymerase-1 (PARP-1) in the early stage of colorectal carcinogenesis.
Colorectal carcinogenesis is initiated mainly by aberrant activation of the Wnt signaling pathway, caused by mutation of either APC or beta-catenin (CTNNB1) gene. Poly(ADP-ribose) polymerase-1 (PARP-1) is a highly conserved nuclear enzyme, which binds tightly to DNA and plays a role in DNA repair, recombination, proliferation and genomic stability. It has recently been shown that PARP-1 is a novel co-activator of TCF-4/beta-catenin-evoked gene transactivation and may play a role in colorectal carcinogenesis. The aim of this study was to examine the PARP-1 expression and determine whether it is correlated with the expression of beta-catenin and its target genes such as c-myc, cyclin D1 and matrix metalloproteinase (MMP)-7 in the early stage of sporadic colorectal carcinogenesis. Using the semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), 91 colorectal tumours, including 65 adenomas and 26 submucosal (pT1) cancers, were analysed for the expression of PARP-1, beta-catenin, c-myc, cyclin D1 and MMP-7. Immunohistochemical analysis of PARP-1 and beta-catenin was also performed. PARP-1 mRNA overexpression was detected in 64 (70.3%) of the 91 tumours. PARP-1 overexpression was significantly correlated with tumour size and histopathology. Overexpression of beta-catenin, c-myc, cyclin D1 and MMP-7 mRNA expression was observed in 39.6%, 78.0%, 83.5% and 72.5% of the 91 tumours, respectively. PARP-1 overexpression was correlated significantly with overexpression of beta-catenin, c-myc, cyclin D1 and MMP-7. Correlation of PARP-1 expression with beta-catenin overexpression was also demonstrated by immunohistochemistry. The results suggest that PARP-1, in conjunction with beta-catenin, c-myc, cyclin D1 and MMP-7, plays an important role in the early stage of colorectal carcinogenesis.
Nosho
Katsuhiko
K
First Department of Internal Medicine, Sapporo Medical University, S.-1, W.-16, Sapporo 060-8543, Japan. nosho@sapmed.ac.jp
Yamamoto
Hiroyuki
H
Mikami
Masashi
M
Taniguchi
Hiroaki
H
Takahashi
Taiga
T
Adachi
Yasushi
Y
Imamura
Akimichi
A
Imai
Kohzoh
K
Shinomura
Yasuhisa
Y
D000230:Adenocarcinoma / Q000378:metabolism*; D000236:Adenoma / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D016259:Genes, myc; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D008875:Middle Aged; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D051176:beta Catenin / Q000378:metabolism
D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D051176:beta Catenin; D019938:Cyclin D1; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020783:Matrix Metalloproteinase 7