SPAG5 contributes to the progression of gastric cancer by upregulation of Survivin depend on activating the wnt/β-catenin pathway

https://doi.org/10.1016/j.yexcr.2019.03.024Get rights and content

Highlights

  • High SPAG5 expression were closely associated with the malignant phenotype and shorter survival in patients with GC.

  • Knockdown of SPAG5 inhibits GC tumor growth in vivo and in vitro.

  • Survivin is crucial for SPAG5-mediated GC progression.

  • SPAG5 contributes to the progression of GC through enhancing the Wnt/β-catenin/Survivin axis.

Abstract

The sperm-associated antigen 5 (SPAG5) plays a key role in controlling cellular processes, including cell cycle progression and proliferation. However, the role of SPAG5 in gastric cancer (GC) remains unclear. Herein, our study showed that upregulation of SPAG5 was detected frequently in GC tissues, and was associated with significantly worse survival in patients with GC. Multivariate analyses revealed that high SPAG5 expression was an independent predictive marker for the poor prognosis of GC patients. Further, SPAG5 knockdown notably inhibited the proliferation abilities of GC in vivo and in vitro. Moreover, our results indicate that SPAG5 promotes cell progression by increasing Survivin expression, which has been reported to control the progression of GC. Moreover, our data demonstrate that Survivin is crucial for SPAG5-mediated GC cell progression in vitro and in vivo. Mechanistically, we demonstrated that SPAG5 promotes the progression of GC via enhancing the Wnt/β-catenin/Survivin axis. Collectively, our data suggest that SPAG5 plays a crucial oncogenic role in GC tumorigenesis, and we provide a novel evidence that SPAG5 may be serve as a prognostic and therapeutic target for GC patients.

Introduction

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide and the most common malignant tumors of gastrointestinal tract in China [1,2]. Although the clinical treatment of GC has been improved, the treatment of GC is still challenging due to the difficulty in early detection of GC and complexities of the disease [3,4]. Therefore, it is key to investigate novel diagnostic markers that govern the occurrence and development of GC to elucidate the process of GC and develop effective GC treatments.

Sperm-associated antigen 5 (SPAG5) was identified as a microtubule-associated protein that was associated with spindles throughout mitosis and localized to kinetochores of congressed chromosomes [5]. SPAG5 has been implicated in cell growth and survival. The imbalance of SPAG5 can cause abnormal changes in cell cycle, apoptosis and immune response [[5], [6], [7]]. Recently, there have been an increasing number of studies on SPAG5 in malignant tumors. The SPAG5 gene is overexpressed in various cancers, such as breast cancer, lung cancer, bladder urothelial carcinoma, hepatocellular carcinoma and cervical cancer [8,9]. Overexpression of SPAG5 is associated with the growth and progression of tumors [8,9]. These studies suggest that SPAG5 may play an important role in tumorigenesis. However, the role of SPAG5 in the process of GC progression is still unclear.

Survivin is a small protein that belongs to the inhibitor of apoptosis family [10,11]. Recent studies have reported that Survivin functions as an oncogene and plays an important role in the tumor progression [12]. Survivin is abundantly expressed in tumors compared with adult differentiated tissues, being associated with poor prognosis in multiple tumor tissues [[13], [14], [15], [16], [17]]. Accumulating evidence has demonstrated that Survivin is overexpressed in colon cancer, liver cancer, lung cancer, cervical carcinoma, and gastric cancer [[13], [14], [15], [16], [17]]. Recently emerging evidence links the biological function of Survivin to gastric cancer carcinogenesis and progression. For example, the downregulation of Survivin inhibits gastric cancer proliferation, whereas increased Survivin expression promotes cell proliferation in gastric cancer [[18], [19], [20]]. However, the regulatory mechanisms of Survivin in GC are not yet clear.

Here, we found that high SPAG5 level is closely related with progression and poor outcome of patients with gastric cancer. Furthermore, SPAG5 knockdown notably inhibits cell growth and induces cell apoptosis in GC cells. Additionally, our results demonstrate that SPAG5 promotes cell progression by increasing Survivin expression, and Survivin is crucial for SPAG5-mediated GC cell progression in vitro and in vivo. Mechanistically, we found that SPAG5 promotes the progression of GC via upregulating Survivin depended on the Wnt/β-catenin signaling pathway. Therefore, we identified that SPAG5 as a novel regulator of GC development and this may provide a potential therapeutic target for GC patients.

Section snippets

Patients and sample collection

All primary GC tissues and corresponding non-tumor tissues were obtained from 165 patients at the Department of General Surgery, Suqian First Hospital and Department of General Surgery, Nantong University Affiliated Hospital, between May 2010 and January 2018. All specimens from resection surgery were frozen and stored at −80 °C for further analysis. The identification of tumor tissues and adjacent normal tissues were confirmed by the pathologists. Informed consent was obtained from each

SPAG5 is significantly upregulated in GC tissues

The role of SPAG5 in gastric cancer remains unknown. Here we aimed to investigate the function of SPAG5 in the development of GC. To this end, we initially explored the expression pattern of SPAG5 in GC tissue and the adjacent non-tumor tissues. We found that the mRNA expression level of SPAG5 was significantly elevated in tumors compared with matched adjacent non-tumor tissue (Fig. 1A). Importantly, the online database Gene Expression Profiling Interactive Analysis (GEPIA, //gepia.cancerpku.cn/index.html

Discussion

SPAG5 is a potent oncogene and plays a crucial role in metastasis of several tumors [[5], [6], [7]]. In this study, we investigated the novel potential tumor promotion role of SPAG5 in human gastric cancer. We found that the expression level of SPAG5 was obviously elevated in tumors obtained from patients with GC, compared with that in the adjacent normal tissues. Importantly, high SPAG5 expression was closely associated with TNM stage and shorter overall survival in GC patients. Multivariate

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgments

This study was supported by grants from the Project of science and technology support of JiangSu Provincial (No. 20175452B).

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