Abstract
Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) has been studied to be involved in the development and progression of several human malignancies. However, little is unveiled regarding the complex mechanisms of TNFRSF11B in human gastric cancer (GC). The clinical significance of TNFRSF11B was assessed in 70 and 160 GC tissues using immunohistochemistry method and gene microarray analysis, respectively. The biological function of TNFRSF11B was studied in vitro and in vivo assays. Immunofluorescence assay was used to evaluate the expression of β-catenin in the nucleus. The expression of β-catenin and related protein was determined by Western blot. The interaction between TNFRSF11B and GSK3β was detected by co-immunoprecipitation. We demonstrated that TNFRSF11B was highly expressed in the cytoplasm of GC and associated with the patient poor outcome. Our studies showed that TNFRSF11B in GC cells significantly promoted cell proliferation, migration, invasion in vitro and tumorigenic ability in vitro and in vivo. Meanwhile, TNFRSF11B inhibited GC cell apoptosis. The proportion of nuclear active β-catenin showed positively correlation with TNFRSF11B expression. TNFRSF11B directly combined with GSK-3β upregulating its phosphorylation, and increased expression of β-catenin and its downstream effectors. Collectively, these findings demonstrate that TNFRSF11B promote the aggressive phenotypes of GC cells and activated Wnt/β-catenin signaling. Accordingly, TNFRSF11B had potential as a biomarker and inhibition of TNFRSF11B expression might offer a new therapeutic target for GC patients.
Highlights
Gastric cancer (GC) is the fifth most common type of cancer in the world and the third dominating cause of cancer-related deaths [1].The early stages of gastric cancer are usually asymptomatic or just nonspecific symptoms
We found that the expression of TNFRSF11B was higher in all of the gastric cancer tissues compared with normal tissues, suggesting that TNFRSF11B may be a crucial factor in gastric cancer (Fig. 1A and B)
To elucidate the role of TNFRSF11B in the carcinogenesis of gastric cancer, we analyzed the relationship between TNFRSF11B expression and the clinicopathological characteristics of gastric cancer patients (Table 1).The frequency of TNFRSF11B expression increased remarkably with the progression of tumor node metastasis (TNM) stage (Fig.1D)
Summary
Gastric cancer (GC) is the fifth most common type of cancer in the world and the third dominating cause of cancer-related deaths [1].The early stages of gastric cancer are usually asymptomatic or just nonspecific symptoms. Adenocarcinoma is the major type of GC. It can be further subdivided into intestinal and diffuse types according to Lauren’s classification [3]. It is a member of the tumor necrosis factor http://www.ijbs.com receptor super family (TNFRSF). It is a secreted protein and a soluble decoy receptor for tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). TNFRSF11B was initially found to bind to the nuclear factor-kappa B(NF-kB) receptor activator, thereby promoting the homeostasis of bone metabolism [6]
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