Cancer Letters

Cancer Letters

Volume 297, Issue 1, 1 November 2010, Pages 9-17
Cancer Letters

Gankyrin promotes the proliferation of human pancreatic cancer

https://doi.org/10.1016/j.canlet.2010.04.019Get rights and content

Abstract

Previous studies in our laboratory have suggested that gankyrin expression is correlated with a malignant phenotype in colorectal cancer. Here, we investigated the possible role of gankyrin in pancreatic carcinogenesis. Gankyrin expression was significantly increased in pancreatic cancer compared to non-cancerous tissues. This expression significantly enhanced cancer cell proliferation and growth in vitro and in vivo. Suppression of gankyrin downregulated cyclin A, cyclin D1, cyclin E, CDK2, CDK4, PCNA and p-Rb but upregulated p27, Rb and p53. However, gankyrin overexpression led to opposite results. Thus, gankyrin could enhance pancreatic cancer cell proliferation by promoting cell cycle progression and p53 degradation.

Introduction

Pancreatic cancer is one of the most common fatal malignancies and is the fourth leading cause of death due to cancer in the US [1]. Despite considerable advances in neoadjuvant chemotherapy, surgical techniques and perioperative care, the prognosis for pancreatic cancer has not improved significantly in the last 20 years [2]. Although many genes and molecular pathways have been reported to be involved in pancreatic carcinogenesis, it is important to identify new oncogenes and therapeutic targets to improve the survival rate of patients with pancreatic cancer [3].

The gankyrin gene is located on human chromosome Xq22.3 [4]. It encodes an oncoprotein with seven ankyrin repeats and is highly conserved in all mammals [5], [6]. It was previously thought that gankyrin was negatively or weakly expressed in normal organs of the digestive system but overexpressed in tumor tissues, such as those of hepatocellular carcinoma (HCC), esophageal squamous cell carcinoma (ESCC) and colorectal cancer. Gankyrin is more commonly overexpressed in HCC than in normal hepatic tissues [7], and it could play an important role mainly at the early stages of human hepatocarcinogenesis [8]. It also leads to cell cycle progression in normal hepatocytes and is important for liver regeneration of patients with fulminant hepatic failure [9]. In human esophageal squamous cell carcinoma, its overexpression is associated with poor prognosis [10]. Intriguingly, previous studies in our laboratory found a direct correlation between the gankyrin expression and the malignant phenotype of colorectal cancer [11]. These findings suggested that gankyrin might be an important protein that is involved in carcinogenesis. Gankyrin, a subunit of the 26S proteasome that interacts with the S6 ATPase of the 26S proteasome [12], was thought to enhance tumor cell proliferation by controlling the phosphorylation of the retinoblastoma protein (pRb) and cyclin D-dependent kinase CDK4 and by increasing p53 ubiquitylation through the RING ubiquitin ligase Mouse Double Minute 2 (MDM2) [13]. However, the role of gankyrin in pancreatic carcinogenesis remains unknown.

In this study, we show for the first time that gankyrin is overexpressed in pancreatic cancer. The upregulation of gankyrin in pancreatic cancer could enhance cell proliferation and growth in vitro and promote tumorigenesis in vivo. Our study indicates that gankyrin could promote cell cycle progression by regulating certain cell cycle effectors of pancreatic cancer.

Section snippets

Tissue collection

A total of 64 formalin-fixed, paraffin-embedded specimens of primary pancreatic cancer and matched adjacent non-cancerous tissues were obtained from patients undergoing surgery at our hospital. Nine fresh tumors and the adjacent non-cancerous tissues were immediately stored at −70 °C in a liquid nitrogen canister until further use. All tumors were diagnosed as pancreatic cancer by the Department of Pathology in our hospital. All patients gave their informed consent to use excess specimens for

Gankyrin expression was significantly increased in pancreatic cancer

Gankyrin expression was evaluated by immunohistochemistry in 64 primary pancreatic cancer tissues and matched adjacent non-cancerous tissues. Gankyrin was mainly located in both the cytoplasm and nuclei of cells (Fig. 1). As shown in Table 1, gankyrin staining was positive in 46 (71.9%) pancreatic cancer tissue samples and five (7.8%) non-tumor tissue samples (P < 0.01). The average score in pancreatic cancer tissues was significantly higher than that in matched non-cancerous tissues (7.27 ± 3.33

Discussion

Despite considerable advances in neoadjuvant chemotherapy, surgical techniques and perioperative care, pancreatic cancer remains a clinical challenge due to the absence of effective methods for early diagnosis and the highly proliferative and invasive features of pancreatic cancer cells. Although several genes and molecular pathways have been identified as being involved in pancreatic carcinogenesis, additional efforts are needed to find new markers for early diagnosis and therapeutic targets.

Conflict of interest

None declared.

Acknowledgements

We would like to thank Professor Jun Fujita for the full-length human gankyrin vector (PhkitNeo-hGankyrin). This study was supported in part by Grants from the National Scientific Foundation of China (30801330).

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    These authors contributed equally to this work.

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