Abstract
Purpose Radiotherapy has been widely applied for the treatment of locally advanced and metastatic gastric adenocarcinoma (GAC). The aberrant expression of secreted phosphoprotein 1 (SPP1) is involved in radiosensitivity in a variety of cancers. The present study aims to characterize the clinical significance of SPP1 expression in GAC and its role and underlying mechanism of radiosensitivity. Methods The SPP1 expression in GAC tissues and pericarcinomatous tissues was determined by QRT-PCR and immunohistochemistry, and the SPP1 expression in GAC cell lines (BGC823, AGS, and SGC7901) and normal human gastric epithelial cell line (GES-1) was determined by western blot. T-test, one-way ANOVA, Cox regression model, and Kaplan–Meier plotter were applied to further assess the association between SPP1 expression and the prognosis of the patients with GAC. After irradiation and transfection with si-SPP1 combined with or without Wnt/β-catenin pathway inhibitor (XAV939), western blot, transwell, flow cytometry, and TOP-flash reporter assay were applied to detect DNA damage, invasion, apoptosis, cell cycle, and activation of Wnt/β-catenin pathway, respectively. Results SPP1 mRNA and protein levels in GAC tissues were both dramatically higher than those in pericarcinomatous tissues. SPP1 overexpression was positively associated with tumor size, nodal status, and histological grade of GAC patients. SPP1 overexpression, depth of invasion, and nodal status were independent prognostic factors for the patients. High SPP1 expression was negatively related to the overall survival in patients with GAC. We found that SPP1 knockdown enhanced the radiosensitivity of GAC cell lines (AGS and SGC7901). Increasing H2AX phosphorylation, apoptosis and G2/M phase arrest, and decreasing invasion were observed after the administration of si-SPP1 and irradiation. Radiosensitivity of SPP1 was mainly dependent on the Wnt/β-catenin signal pathway. XAV939 could enhance these phenomena induced by irradiation combined with SPP1 knockdown. Conclusion This study demonstrates that SPP1 suppresses Wnt/β-catenin signaling to enhance the radiosensitivity of GAC via inhibiting invasion and accelerating DNA damage, G2/M phase arrest, and apoptosis.
Highlights
Gastric cancer (GC) is an aggressive malignancy with an extremely poor prognosis and a high incidence [1]. e incidence of gastric adenocarcinoma (GAC) accounts for 95 percent of gastric malignant tumors [2]
Secreted phosphoprotein 1 (SPP1) was overexpressed in GAC tissues compared with normal gastric tissues (p < 0.01, Figure 1(a)). is result was confirmed by detecting the level of SPP1 protein
Radiotherapy has been widely applied for the treatment of locally advanced and metastatic GAC [14, 15]. e search for an effective gene target to enhance the sensitivity of radiotherapy is a vital and urgent issue for the therapy of GAC
Summary
Gastric cancer (GC) is an aggressive malignancy with an extremely poor prognosis and a high incidence [1]. e incidence of gastric adenocarcinoma (GAC) accounts for 95 percent of gastric malignant tumors [2]. Gastric cancer (GC) is an aggressive malignancy with an extremely poor prognosis and a high incidence [1]. E incidence of gastric adenocarcinoma (GAC) accounts for 95 percent of gastric malignant tumors [2]. Because of the low radiosensitivity of GC, no difference in survival was observed in GAC patients receiving radiotherapy [5, 6]. High plasma concentrations of SPP1 are correlated with a poor prospect for patients with head and neck cancer after. High SPP1 expression level at the end of radiotherapy is correlated with poor survival, such as glioma [12] and non-small-cell lung cancer [13]. The role of SPP1 in radiosensitivity in GAC remains unclear. The association between SPP1 and radiosensitivity in GAC needs to be investigated further
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