Overexpression of poly(ADP-ribose) polymerase-1 (PARP-1) in the early stage of colorectal carcinogenesis
Introduction
Colorectal cancer is one of the most common human malignancies in the world. Although alternative pathways exist, it is generally accepted that most colorectal carcinomas arise in pre-existing adenomas.1
Aberrant transactivation of T cell factor (TCF)-4-regulated genes by β-catenin plays a key role in colorectal carcinogenesis.1 APC dysfunction or abnormalities of the β-catenin gene result in cytoplasmic accumulation of unphosphorylated β-catenin. This stabilized β-catenin protein translocates into the nucleus where, it modulates gene transcription by interacting with TCF-4, resulting in transcriptional activation of target genes such as c-myc, cyclin-D1 and matrix metalloproteinase (MMP)-7 (matrilysin).2 Thus, the β-catenin/TCF-4 complex and its associated molecules appear to be candidates for targets of molecular therapy against colorectal cancer. In this regard, it is notable that poly(ADP-ribose) polymerase-1 (PARP-1) was recently identified as a novel co-activator of TCF-4/β-catenin-evoked gene transactivation.3
PARP-1 is a highly conserved nuclear enzyme that binds tightly to DNA and plays a role in DNA repair, recombination, proliferation and genomic stability.4, 5, 6 Although PARP-1 has been thought to play a protective role against carcinogenesis, no mutation or loss of heterozygosity (LOH) of the PARP-1 gene has been reported in clinical cancer tissues. On the other hand, overexpression of PARP-1 has been reported in various human malignancies, such as malignant lymphoma,7 breast carcinoma,8 Ewing’s sarcoma,9 hepatocellular carcinoma10 and endometrial carcinoma.11 Importantly, aberrant poly(ADP-ribose) metabolism, including enhanced PARP activity and poly(ADP-ribose) synthesis, has been shown by biochemical and immunohistochemical analyses in human colon adenoma and carcinoma.12
Recently, Idogawa and colleagues3 reported that PARP-1 physically interacted with TCF-4 and augmented the transcriptional activity of the β-catenin/TCF-4 complex. Knockdown of PARP-1 by RNA interference (RNAi) significantly suppressed both transcriptional activity and proliferation of colorectal cancer cells. PARP-1 was strongly expressed in nuclei of adenoma cells in the large intestine of all 10 patients with familial adenomatous polyposis (FAP) analysed and in the small and large intestines of Min mice. Notably, the expression pattern of PARP-1 in adenoma cells completely parallelled that of accumulated β-catenin protein. Therefore, the expression patterns and functional properties of PARP-1 suggest that PARP-1 plays a role in colorectal carcinogenesis.3, 12 PARP-1 overexpression has been detected in 23 (82.1%) of 28 sporadic colorectal carcinoma tissues.3 Although enhanced PARP-1 activity and poly(ADP-ribose) synthesis have been reported in a small number of sporadic colon adenoma tissues,12 it is not known whether PARP-1 overexpression is correlated with β-catenin in sporadic colorectal adenoma.
In an attempt to address these issues, we investigated the expression of PARP-1, β-catenin, c-myc, cyclin D1 and MMP-7 in 91 early colorectal tumour tissues, including 65 adenoma tissues and 26 cancer tissues with submucosal invasion (pT1), by using the semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). We further analysed immunohistochemically the expression of PARP-1 and β-catenin.
Section snippets
Patients and tissue samples
Ninety-one paired specimens of colorectal tumour and non-tumour tissues were obtained by polypectomy or surgical treatment. These tumour samples consisted of 65 adenomas and 26 adenocarcinomas with submucosal invasion (pT1 in the TNM classification of the Union International Contre Cancer) (Table 1). Additionally, seven hyperplastic polyp tissues were obtained by endoscopy. Each tissue specimen was divided into two pieces. For total RNA extraction, one sample was immediately frozen in liquid
PARP-1 and β-catenin mRNA expression in colorectal tumour tissues
To perform semi-quantitative RT-PCR analysis, the ranges of linear amplification for each target gene and for the control GAPDH gene were examined. The optimal number of PCR cycles and optimal mixing ratios of primers were determined. The expression of PARP-1 and β-catenin mRNA in 91 colorectal tumour tissues was examined. Fig. 1 shows the representative results. PARP-1 mRNA expression was detected in 64 (70.3%) of the 91 colorectal tumour tissues but was only faintly detected in adjacent
Discussion
The issue that we addressed in this study was the expression of PARP-1 and its relationship with the expression of β-catenin and its target genes, such as c-myc, cyclin D1 and MMP-7, in the early stage of colorectal carcinogenesis. The reason why we chose pT1 cancer is that it represents the early stage of colorectal cancer.
PARP-1 mRNA overexpression was detected in 64 (70.3%) of the 91 colorectal adenoma and pT1 cancer tissues but was only faintly detected in adjacent non-tumour tissues and
Ethics approval statement
An informed consent was obtained from each patient and the institutional review committee approved this study.
Conflict of interest statement
None declared.
Acknowledgements
This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (H.Y. and K.I.) and Grants-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan (H.Y. and K.I.).
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