PARP-1 Expression is Increased in Colon Adenoma and Carcinoma and Correlates with OGG1

<div><p>The ethiology of colon cancer is largely dependent on inflammation driven oxidative stress. The analysis of 8-oxodeoxyguanosine (8-oxodGuo) level in leukocyte DNA of healthy controls (138 individuals), patients with benign adenomas (AD, 137 individuals) and with malignant carcinomas (CRC, 169 individuals) revealed a significant increase in the level of 8-oxodGuo in leukocyte DNA of AD and CRC patients in comparison to controls. The counteracting mechanism is base excision repair, in which OGG1 and PARP-1 play a key role. We investigated the level of PARP-1 and OGG1 mRNA and protein in diseased and marginal, normal tissues taken from AD and CRC patients and in leukocytes taken from the patients as well as from healthy subjects. In colon tumors the PARP-1 mRNA level was higher than in unaffected colon tissue and in polyp tissues. A high positive correlation was found between PARP-1 and OGG1 mRNA levels in all investigated tissues. This suggests reciprocal influence of PARP-1 and OGG1 on their expression and stability, and may contribute to progression of colon cancer. PARP-1 and OGG1 proteins level was several fold higher in polyps and CRC in comparison to normal colon tissues. Individuals bearing the <i>Cys326Cy</i>s genotype of OGG1 were characterized by higher PARP-1 protein level in diseased tissues than the <i>Ser326Cys</i> and <i>Ser326Se</i>r genotypes. Aforementioned result may suggest that the diseased cells with polymorphic OGG1 recruit more PARP protein, which is necessary to remove 8-oxodGuo. Thus, patients with decreased activity of OGG1/polymorphism of the OGG1 gene and higher 8-oxodGuo level may be more susceptible to treatment with PARP-1 inhibitors.</p></div

Comparison of the level of PARP-1 protein expression in relation to OGG1polymorphism.

<p>Center mark in the box indicates medians for samples. The length of each box (IQR, interquartile range) represents the range within which the central 50% of the values fell, with the vertical edges placed at the first and third quartiles. Whiskers show variability outside the upper and lower quartiles. <i>P</i> was obtained with the Mann-Whitney test.</p

Correlation between PARP-1 and OGG1 mRNA levels in leukocytes of healthy volunteers (A), adenoma patients (B) and carcinoma patients (C), as well as in polyp tissue (D), normal colon (E) and tumor (F).

<p>Correlation between PARP-1 and OGG1 mRNA levels in leukocytes of healthy volunteers (A), adenoma patients (B) and carcinoma patients (C), as well as in polyp tissue (D), normal colon (E) and tumor (F).</p

Level of PARP-1 (A) and OGG1 (B) mRNA in normal colon tissue (n = 60), polyp (n = 24) and cancer tissue (n = 60).

<p>Center mark in the box indicates the medians of the samples. The length of each boxes (IQR, interquartile range) represents the range within which the central 50% of the values fell, with the vertical edges placed at the first and third quartiles. Whiskers show variability outside the upper and lower quartiles. <i>P</i> was obtained with the Mann-Whitney test.</p

Comparison of the expression of OGG1 (A) and PARP-1 (B) protein in normal colon tissue, polyp and cancer tissue of adenoma (AD, n = 68) and carcinoma (CRC, n = 103) patients.

<p>Immunohistochemical detection in paraffin embedded sections stained with hematoxylin and eosin. Center mark in the box indicates the medians of the samples. The length of each box (IQR, interquartile range) represents the range within which the central 50% of the values fell, with the vertical edges placed at the first and third quartiles. Whiskers show variability outside the upper and lower quartiles. <i>P</i> was obtained with the Mann-Whitney test. Representative examples of the levels of PARP-1 protein in tissues of CRC patients determined by Western analysis. The analysis was performed on tumor and normal tissues of 41 CRC patients (C).</p