Ribonucleotide Reductase Subunits M2 and p53R2 are Potential Biomarkers for Metastasis of Colon Cancer

Abstract

Ribonucleoside diphosphate reductase plays a key role in converting ribonucleoside diphosphate to 2'-deoxyribonucleoside diphosphate, which is necessary for DNA repair and replication. To determine if human ribonucleotide reductase small subunit M2 (hRRM2) and p53-dependent human ribonucleotide reductase small subunit R2 (p53R2) play roles on invasion ability of cancer cells, the gene transferring technique was used to construct stable hRRM2 and p53R2 overexpression transfectants. Increase of hRRM2 dramatically enhanced the cell migration in KB and PC-3 cells, but p53R2 overexpression reduced cellular invasion potential to 50% and 40% in KB and PC-3 cells, respectively. Furthermore, hRRM2 enhanced cancer cells to induce the cell migration of Human Umbilical Vein Endothelial Cells, but p53R2 reduced this ability in transfectants. To further determine the role of human ribonucleotide reductase subunits on cancer metastasis, a tissue array, including 59 primary and 49 metastatic colon adenocarcinoma samples, was used. Immunohistochemistry was used to evaluate the relationship between human ribonucleotide reductase subunits and metastasis. Univariate and multivariate analysis revealed that p53R2 is negatively related to the metastasis of colon adenocarcinoma samples (odds ratio, 0.23; P < 0.05); hRRM2 increases the risk of metastasis in colon cancer, but did not show significantly. Thus, opposing regulation of hRRM2 and p53R2 in invasion potential might play a critical role in determining the invasion and metastasis phenotype in cancer cells. The expression level of ribonucleotide reductase small subunits could serve as biomarkers to predict the malignancy potential of human cancers in the future.