Elsevier

Human Pathology

Volume 56, October 2016, Pages 171-177
Human Pathology

Original contribution
G-protein-coupled receptor kinase 2 in pancreatic cancer: clinicopathologic and prognostic significance,☆☆

https://doi.org/10.1016/j.humpath.2016.06.012Get rights and content

Summary

G-protein-coupled receptor kinase 2 (GRK2) was found to regulate biological behaviors in some cancers, including pancreatic cancer (PC). However, its clinicopathologic and prognostic implications in cancer remain unclear. This study was designed to address the issues in PC. Expression of GRK2 was measured by Western blotting and tissue microarray–based immunohistochemical staining in 3 and 171 patients with PC, respectively. The H-score was used to evaluate the staining results. In addition, GRK2 expression was correlated with clinicopathologic variables and overall survival. Finally, the prognostic value of GRK2 was validated in a publically available PC dataset, GSE21501. It was suggested that GRK2 expression was highly up-regulated in 2 out of 3 tumor samples, in contrast to corresponding non-tumor ones. Furthermore, H-score of GRK2 staining was significantly higher in tumor than in non-tumor tissues. Tumoral expression of GRK2 was significantly associated with T stage. Univariate analysis showed that high GRK2 expression in tumor tissues was predictive for poor overall survival of PC. However, GRK2 expression was not identified as an independent prognostic marker in multivariate Cox regression test, although close to the statistical significance. In dataset GSE21501, GRK2 was also revealed to be prognostic. Our data establish that GRK2 is overexpressed in PC, and might serve as a potential indicator of unfavorable prognosis.

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.

Section snippets

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.

. The influence of GRK2 expression on cumulative survival in the publically available dataset of PC, GSE21501 (P = .02079, log-rank test).

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    Disclosures: None declared.

    ☆☆

    Funding/Support: National Natural Science Foundation (81 272 573) and National High Technology Research and Development Program (863 Program, 2012AA02A212), China.

    1

    These authors contributed equally to this study.

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