Original contributionG-protein-coupled receptor kinase 2 in pancreatic cancer: clinicopathologic and prognostic significance☆,☆☆
Introduction
It has been well recognized that pancreatic cancer (PC) is one of most lethal malignant neoplasms, because of its extremely dismal overall prognosis [1]. Therefore, its prognostic factors are long of interest. Thus far, many clinical and pathologic variables that affect prognosis of PC, such as lymph node involvement, tumor differentiation, tumor (T) and node (N) stages according to tumor-node-metastasis classification [2], as well as carbohydrate antigen (CA) 19-9 level, have been identified [3], [4], [5], [6], [7]. Within recent years, biological prognostic markers of PC, on the basis of molecules that have been proven to play important roles in initiation and progression of cancer, have been extensively studied and summarized [8], [9]. Of course, more candidates remain to be accumulated.
G protein-coupled receptor kinase 2 (GRK2), an isoform of GRKs that catalyze phosphorylation and desensitization of agonist-bound G protein-coupled receptors [10], [11], was suggested to play important roles in regulation of cell phenotypes and relative signaling pathways [12], [13], [14], [15], [16]. In many kinds of human malignant neoplasms, such as bladder cancer [17], thyroid carcinoma [18], hepatocellular carcinoma [19], [20], breast cancer [21] and Kaposi's sarcoma [22], GRK2 was found to be associated with favorable biological behaviors, indicating its possible role as a tumor suppressor gene. However, the effect of this gene in PC might be a counterexample [23]. In this report, GRK2 was one of novel functionally relevant target genes identified using a multistep high-content screening approach, and was shown to be up-regulated and to accelerate tumor growth in PC [23]. Therefore, GRK2 might function in a tissue type–specific manner. So far, clinicopathologic and prognostic significances of GRK2 in cancer have not been explored.
In the present study, expression, clinicopathologic and prognostic roles of GRK2 in PC were investigated in Chinese patients. In addition, its prognostic value was validated in the publically available dataset, GSE21501.
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Patients
Three PC patients (2 men and 1 woman; 52-65 years; median: 60 years) whose samples were collected for Western blotting and 171 (107 men and 64 women; 35 to 85 years; median: 62 years) whose specimens were used in immunohistochemistry were enrolled in this study. Histological parameters, including differentiation grade, perineural invasion, T and N stages were determined by post-surgical pathologic examinations. The Institutional Ethics Committee approval for the project (S-745) and the informed
Expression of GRK2 in tumor and non-tumor tissues of PC
Western blotting analysis established that GRK2 expression was highly up-regulated in 2 out of 3 tumor samples, in contrast to corresponding non-tumor ones (Fig. 1). Using immunohistochemical staining, it was shown that the positive signal was mainly located in the cytoplasm (Fig. 2A-H). The median H-score of GRK2 was 90 (range, 0-190) in tumor tissues and 49 (range, 0-190) in non-tumor ones, respectively. The H-score of GRK2 was significantly higher in tumor than in non-tumor tissues (P < .001,
Discussion
It is known that GRK2 is one of isoforms of GRKs that has proven to play crucial roles in regulation of cell phenotypes, such as cell spreading and migration, and corresponding signaling pathways [12], [13], [14], [15], [16], through phosphorylating and desensitizing G protein-coupled receptors [10], [11]. Within the last decade, GRK2 was established to have a favorable impact on biological behaviors of a line of human malignant tumors [17], [18], [19], [20], [21], [22]. These works support its
Supplementary data
The following is the Supplementary data to this article.
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Disclosures: None declared.
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Funding/Support: National Natural Science Foundation (81 272 573) and National High Technology Research and Development Program (863 Program, 2012AA02A212), China.
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These authors contributed equally to this study.