Replication protein A is an independent prognostic indicator with potential therapeutic implications in colon cancer

Abstract

Replication protein A (RPA), a component of the origin recognition complex, is required for stabilization of single-stranded DNA at early and later stages of DNA replication being thus critical for eukaryotic DNA replication. Experimental studies in colon cancer cell lines have shown that RPA protein may be the target of cytotoxins designed to inhibit cellular proliferation. This is the first study to investigate the expression of RPA1 and RPA2 subunits of RPA protein and assess their prognostic value in colon cancer patients. We analyzed immunohistochemically the expression of RPA1 and RPA2 proteins in a series of 130 colon cancer resection specimens in relation to conventional clinicopathological parameters and patients' survival. Statistical significant positive associations emerged between: (a) RPA1 and RPA2 protein expressions (P ¼ 0.0001), (b) RPA1 and RPA2 labelling indices (LIs) and advanced stage of the disease (P ¼ 0.001 and 0.003, respectively), (c) RPA1 and RPA2 LIs and the presence of lymph node metastasis (P ¼ 0.002 and 0.004, respectively), (d) RPA1 LI and the number of infiltrated lymph nodes (P ¼ 0.021), (e) RPA2 LI and histological grade of carcinomas (P ¼ 0.05). Moreover, a statistical significant higher RPA1 LI was observed in the metastatic sites compared to the original ones (P ¼ 0.012). RPA1 and RPA2 protein expression associated with adverse patients' outcome in both univariate (log rank test: Po0.00001 and 0.00001, respectively) and multivariate (Cox model: P ¼ 0.092 and 0.0001, respectively) statistical analysis. Statistical significant differences according to the expression of RPA1 and RPA2 proteins were also noticed in the survival of stage II (Po0.00001 and 0.0016, respectively) and stage III (P ¼ 0.0029 and 0.0079, respectively) patients. In conclusion, RPA1 and RPA2 proteins appear to be useful prognostic indicators in colon cancer patients and attractive therapeutic targets for regulation by tumor suppressors or other proteins involved in the control of cell proliferation. Modern Pathology (2007) 20, 159-166.

An Alternative Form of Replication Protein A Expressed in Normal Human Tissues Supports DNA Repair

“…In three of the four tissues compared, the levels of RPA2 mRNA increased. This is in agreement with the literature that has found increased expression of RPA in metastatic cancers (44,45). These data, together with the finding that RPA4 is not expressed at significant levels in stable cultured cell lines, suggests that RPA4 is down-regulated in transformed cells.…”

TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer

“…Although SNAP25 has not earlier been described in prostate, it has an established role in membrane trafficking and exocytosis for hormone secretion in other tissues, such as the pancreas (Sadoul et al, 1995). The basal cell profile was consistent with a proliferative phenotype, with expression of CXCL1, NBS1 and RPA, all of which encode proteins shown earlier to promote proliferation (Chiang et al, 2003;Li et al, 2004;Givalos et al, 2007). The expression of aV integrin has earlier been described in metastatic prostate cancer (McCabe et al, 2007) but not in benign prostate cells, where it may have a role in adhesion to the basement membrane.…”

TSPAN1 protein expression: A significant prognostic indicator for patients with colorectal adenocarcinoma

“…The other molecules studied include MST1 (Mammalian sterile 20-like kinase) [6] . Replication protein (RPA) [7] , ELAV-like protein Huk and COX-2 [8] , a-catenin, b-catenin [9] a-ligatin, b-ligatin, Rho-a [10] , etc. In fact, an established cascade of events leading to colorectal cancer development and progression is described by Vogelstein.…”