FBXO2, a novel marker for metastasis in human gastric cancer

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Highlights

  • We have detected that the level of FBXO2 is highly correlated with lymph node metastasis, and that overall survival (OS) of patients.

  • FBXO2 promoted the proliferation and migration of human gastric cancer cells.

  • Furthermore, Down-regulating FBXO2 reduced epithelial-mesenchymal transition (EMT) in gastric cancer cells.

  • Our study demonstrated that FBXO2 may be a novel target in the diagnosis and treatment of gastric cancer.

Abstract

FBXO2 belongs to the F-box family of proteins, is a cytoplasmic protein and ubiquitin ligase F-box protein with specificity for high-mannose glycoproteins. Recently published studies indicate that other members of the F-box family, such as SKP2 and FBXW7, are involved in the development of gastric cancer. The role of FBXO2 in the process of tumorigenesis, including gastric cancer, is still unknown. In this study, we show that the level of FBXO2 is highly correlated with lymph node metastasis, and that overall survival (OS) of patients with high FBXO2 expression is significantly shorter than patients with low FBXO2 expression. FBXO2 promoted the proliferation and migration of human gastric cancer cells, whereas knockdown of FBXO2 by siRNA led to a decrease in those activities. Down-regulating FBXO2 reduced epithelial-mesenchymal transition (EMT) in gastric cancer cells, with increased expression of E-cadherin and decreased expression of N-cadherin and vimentin. In summary, our findings suggest that FBXO2-regulated EMT led to carcinogenicity in gastric cancer and may be a novel target in the diagnosis and treatment of gastric cancer.

Introduction

Gastric cancer is the fourth most common and the second most lethal cancer worldwide [1,2]. Despite wide application of standardized surgical treatment and better perioperative care, the treatment of gastric cancer at early stages remains a challenge in clinical settings and [3]. Therefore, there is an urgent need to seek for new biomarkers for early diagnosis of gastric cancer and to explore new treatments to improve the survival and health of patients with gastric cancer.

F-box proteins are classified into three families based on the presence of a specific recognition domains [4,5]. Members of this family have been shown to be important in cell cycle regulation, play key roles in tumorigenesis, and exhibit oncogenic or tumor-suppressive activities [[6], [7], [8]]. SKP2 overexpressed in various human tumors [[9], [10], [11]]; high levels of SKP2 is associated with poor prognosis in gastric cancer [9]. FBXW7 acts as a tumor suppressor in the development in many human malignancies [6,[12], [13], [14]]. Low expression of Fbxw7 in gastric cancer is associated with the induction of apoptosis and growth stagnation to inhibit progression [15]. FBXO2 (also referred to as Fbx2, Fbg1, Fbs1, NFB42 and OCP1), a cytoplasmic protein and ubiquitin ligase F-box protein with specificity for high-mannose glycoproteins, is highly enriched in the brain [16,17] and plays an important role in neurological diseases [[18], [19], [20]]. However, while other members of the F-box protein family including SKP2 and perioperative care FBXW7 are known to be involved in the development of gastric cancer, the role of FBXO2 is not known. Due to its potential to act as an agent in tumorigenesis and as a therapeutic target, we determined the role of FBXO2 in gastric cancer.

In the current study, we explore the role of FBXO2 in gastric cancer. We demonstrate that the level of FBXO2 is highly correlated with lymph node metastasis and that OS of patients with high FBXO2 expression is significantly shorter than patients with low FBXO2 expression. We also show that low FBXO2 expression inhibits the growth and metastasis of gastric cancer cells in vitro through the regulation of epithelial–mesenchymal transition (EMT).

Section snippets

Patients

From January 2011 to December 2011, 89 patients were accepted for radical surgery at the affiliated hospital of Jiangnan University. All clinical and pathological information of the 89 patients was recorded, including age, sex, tumor location, tumor staging, tumor differentiation, and AJCC Substage. Overall survival (OS) was the interval from initial surgery to death. We confirm that all 89 patients gave written informed consent.

Cells and cell culture

Human gastric cancer cell lines MGC80-3, AGS, SGC-7901, and MKN-28

Elevated FBXO2 level is associated with lymph node metastasis in gastric cancer

To explore the expression of FBXO2 in gastric cancer, we performed immunohistochemistry (IHC) on 89 gastric cancer tissues. Fig. 1 showed that FBXO2 protein in gastric cancer tissues. We further analyzed the correlation between FBXO2 expression and clinicopathological characteristics. The pathological and clinical characteristics of 89 gastric cancer patients are shown in Table 1. Follow-up period ranges from 5 to 69 months (median = 66 months). It was confirmed that 39 patients died after the

Discussion

In this study, we determined the clinical relevance of FBXO2 in gastric cancer and demonstrated that FBXO2 levels positively associate with lymph node metastasis, suggesting that high expression FBXO2 could predict metastasis in gastric cancer. Metastasis, associated with cancer malignancy and patient death, requires EMT. The occurrence of EMT during tumor progression allows benign tumor cells to acquire the capacity to permeate surrounding tissues and to eventually metastasize to distant sites

Acknowledgements

We thank this work was supported by Jiangsu Province Clinical Medical Science and Technology Specialized Research Fund (No. BL2014019); Key Program from Wuxi Health Bureau (No.Z201401); Natural Science Foundation of Jiangsu Province of China (No.BK20150162); Scientific and Technological Development Fund from Wuxi Science and Technology Bureau (No.CSE31N1419); Key Program from Wuxi Hospital management center (No.YGZXG1406); Jiangsu Province Young Medical Talents (No. QNRC2016153).

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    These authors contributed equally to this work.

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