Ribonucleotide Reductase Small Subunit M2B Prognoses Better Survival in Colorectal Cancer

Abstract

Ribonucleotide reductase subunit RRM2B (p53R2) has been reported to suppress invasion and metastasis in colorectal cancer (CRC). Here we report that high levels of RRM2B expression is correlated with markedly better survival in CRC patients. In a fluorescence-labeled orthotopic mouse xenograft model, we confirmed that overexpression of RRM2B in non-metastatic CRC cells prevented lung and/or liver metastasis, relative to control cells that did metastasize. Clinical outcome studies were conducted on a training set with 103 CRCs and a validation set with 220 CRCs. All participants underwent surgery with periodic follow-up to determine survivability. A newly developed specific RRM2B antibody was employed to perform immunohistochemistry (IHC) for determining RRM2B expression levels on tissue arrays. In the training set, the Kaplan-Meier and multivariate COX analysis revealed that RRM2B is associated with better survival of CRCs, especially in stage IV patients (Hazard ratio, HR=0.40; 95% CI 0.18–0.86, p=0.016). In the validation set, RRM2B was negatively related to tumor invasion (odds ratio, OR=0.45, 95% CI 0.19–0.99, p=0.040) and lymph node involvement (OR=0.48, 95% CI 0.25–0.92, p=0.026). Further, elevated expression of RRM2B was associated with better prognosis in this set as determined by multivariate analyses (HR=0.48, 95% CI 0.26–0.91, p=0.030). Further investigations revealed that RRM2B was correlated with better survival of CRCs with advanced stage III–IV tumors rather than earlier stage I–II tumors. Taken together, our findings establish that RRM2B suppresses invasiveness of cancer cells and that its expression is associated with a better survival prognosis for CRC patients.

Precision Medicine and Pancreatic Cancer

“…(27) Details of the de-paraffinization protocol and IHC were described in a previous publication. (28).…”

“…Cytoplasmic staining of p53R2 protein was assigned a score from 0 to 2 based on staining intensity (no staining = 0, weakly positive staining = 1, and strongly positive staining = 2) per prior study. (27) The percentage of adenocarcinoma cells stained at each intensity level was recorded for each, resulting in a weighted scores ranged between 0 and 200. For the purposes of statistical analysis, the scores were dichotomized into low p53R2 and high p53R2 based on the median score.…”

Nucleotide metabolism, oncogene-induced senescence and cancer

“…In addition, high p53R2 expression is also a poor prognostic biomarker in non-small cell lung cancer [71] and squamous cell carcinoma [73]. However, some studies have indicated that high p53R2 leads to a better prognosis [74, 75]. Future studies will need to be done on larger patient cohorts to truly determine whether p53R2 expression predicts better or worse patient outcome.…”

Soluble Carcinoembryonic Antigen Activates Endothelial Cells and Tumor Angiogenesis

“…To exclude any indirect effects of CEA on angiogenesis such as previously reported CEA binding to NK cells via CEACAM1 (22), we next performed tumor transplants in NSG mice, which are characterized by severe immunodeficiency due to the absence of functional NK cells, absence of mature T and B cells, and deficiency in cytokine signaling (34). As expected, growth of tumor transplants was enhanced in both groups, but CEA-expressing tumors (Meth-A/CEA) grew significantly faster than Meth-A/wt.…”