High Levels of Nucleolar Expression of Nucleolin Are Associated with Better Prognosis in Patients with Stage II Pancreatic Ductal Adenocarcinoma

Abstract

Purpose: Nucleolin is a major nucleolar protein that has been shown to be overexpressed in rapidly dividing cells and plays an essential role in cell proliferation and survival. However, the expression and significance of nucleolin in pancreatic ductal adenocarcinoma (PDA) have not been studied.Experimental Design: We used a tissue microarray consisting of 1.0-mm cores of tumor and paired nonneoplastic pancreatic tissue from 69 pancreaticoduodenectomy specimens with stage II PDA. Nucleolin expression was evaluated by immunohistochemistry and scored quantitatively by image analysis. Nucleolin expression was classified as nucleolin-high or nucleolin-low using the median nucleolin labeling index of 3.5% as cutoff. Staining results were correlated with clinicopathologic features and survival.Results: Both PDAs and PDA cell lines showed nucleolar staining for nucleolin. Nucleolin expression was higher in PDAs and PDA cell lines than in nonneoplastic ductal epithelial cells. Among the 69 stage II PDAs, 34 (49%) were nucleolin-high. The median overall survival was 65.2 ± 16.3 months for patients who had nucleolin-high PDAs compared with 19.5 ± 3.3 months for patients whose tumors were nucleolin-low (P = 0.03, log-rank method). No significant correlation between nucleolin expression and other clinicopathologic parameters was found. In multivariate analysis, nucleolin expression was a prognostic factor for overall survival in patients with stage II PDA independent of patient's age, gender, tumor size, differentiation, and lymph node status.Conclusions: Nucleolin was overexpressed in PDAs and PDA cell lines. A high level of nucleolar expression of nucleolin was an independent prognostic marker for better survival for patients with stage II PDAs. Clin Cancer Res; 16(14); 3734-42. ©2010 AACR.Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States (1). Only 15% to 20% of patients diagnosed with PDA are surgically resectable and most of the patients who undergo resection have stage II disease. The long-term survival rate of patients who have curative resection is approximately 20%, with a median survival of 18 to 24 months (1). Despite pancreaticoduodenectomy, the disease commonly recurs, with the most common sites of recurrence being the liver, lung, peritoneal cavity, and pancreatic surgery bed; the prognosis is poor (1).Previous studies have shown that multiple genes are frequently altered in PDAs, including the activation of the K-ras oncogene by point mutation (2) and inactivation of the tumor suppressor genes p16 (3), SMAD4/ DPC4 (4, 5), and p53 (6). More recently, it has been shown that telomere shortening occurs at the early stage during the development of PDA. Telomere shortening was detected in 91% of the pancreatic intraepithelial neoplasia 1A (PanIN 1A), the earliest putative precursor lesion for PDAs (7). Telomere length is maintained by the human telomerase complex, which is composed of human telomerase RNA (hTR or TERC), and telomeraseassociated protein 1 ...

Cell Surface Nucleolin Facilitates Enterovirus 71 Binding and Infection

“…It controls the metabolism of DNA and RNA in the nucleolus (44,45), shuttles proteins into the nucleus (46), provides posttranscriptional regulation of strategic mRNAs in the cytoplasm (47,48), and serves as a ligand for proteins, such as midkine and the heparin-binding growth-associated molecule, on the cell surface (49). NCL is also involved in the proliferation of many types of cancer (34,(50)(51)(52) and serves as a prognosis marker and therapeutic target for cancer treatment (53)(54)(55). Furthermore, NCL also participates in the pathogenic mechanism and mediates the replication of several viruses and/or serves as a cell surface receptor for Escherichia coli O157 (56), Helicobacter pylori (57), RSV (28), adeno-associated virus type-2 (AAV-2) (58), coxsackie B virus (59), and HIV (29).…”

Increased level of nucleolin confers to aggressive tumor progression and poor prognosis in patients with hepatocellular carcinoma after hepatectomy

“…For example, Qiu et al [12] indicated that the high expression level of nucleolin was an independent prognostic marker for worse survival of patients with gastric cancer; Zhao et al [13] determined that nucleolin expression independently predicted for worse survival of patients with non small cell lung cancer; Grinstein et al [14] identified nucleolin as activator of human papillomavirus type 18 oncogene transcription in cervical cancer; High levels of nucleolin expression have also been shown to correlate with poor survival in patients with cutaneous melanoma and pediatric intracranial ependymoma [15,16]. In contrast, Peng et al [34] reported that high levels of nucleolar expression of nucleolin may be associated with better prognosis in patients with stage II pancreatic ductal adenocarcinoma. Our study revealed that the increased expression of nucleolin was dramatically associated with aggressive clinicopathological features of patients with HCC, such as advance tumor stage, high tumor grade and high serum level of AFP.…”

Quantitative Proteomics Approach to Screening of Potential Diagnostic and Therapeutic Targets for Laryngeal Carcinoma

“…It has been shown to be up-regulated in highly proliferative cells and regulated many aspects of DNA and RNA metabolism, chromatin structure, rRNA maturation, cytokinesis, nucleogenesis, cell proliferation and growth [32], [33]. Further, the expression of NCL was reported to be increased in pancreatic ductal adenocarcinoma and the overexpression of the protein was found in other human cancers such as gliomas, melanoma, and non-small cell lung cancer [34]–[37]. Similarly, our semiquantitative RT-PCR and Western blotting results confirmed on a larger series of specimens the increased expression of NCL in the laryngeal carcinoma, indicating the possibility that the overexpression of this protein is more specific to cancer.…”