TNFRSF11B activates Wnt/β-catenin signaling and promotes gastric cancer progression
TNFRSF11B activates Wnt/β-catenin signaling and promotes gastric cancer progression
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TNFRSF11B 激活 Wnt/β-catenin 信号传导并促进胃癌进展
DOI：
10.7150/ijbs.43630
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发表时间：
2020-01-01
影响因子：
9.2
通讯作者：
Ji, Jiafu
中科院分区：
文献类型：
--
作者：
Luan, Fengming;Li, Xiaomei;Ji, Jiafu
肿瘤坏死因子受体超家族成员 11B (TNFRSF11B) 已被研究参与多种人类恶性肿瘤的发生和进展。然而，关于 TNFRSF11B 在人类胃癌 (GC) 中的复杂机制，目前所知甚少。使用免疫组织化学方法和基因微阵列分析分别评估了 70 例和 160 例 GC 组织中 TNFRSF11B 的临床意义。通过体外和体内测定研究了 TNFRSF11B 的生物学功能。使用免疫荧光测定法评估细胞核中β-连环蛋白的表达。通过Western blot检测β-连环蛋白及相关蛋白的表达。通过免疫共沉淀检测 TNFRSF11B 和 GSK3 β 之间的相互作用。我们证明 TNFRSF11B 在 GC 细胞质中高表达，并与患者不良预后相关。我们的研究表明，GC细胞中的TNFRSF11B显着促进细胞增殖、迁移、体外侵袭以及体外和体内的致瘤能力。同时，TNFRSF11B抑制GC细胞凋亡。核活性β-catenin比例与TNFRSF11B表达呈正相关。 TNFRSF11B 直接与 GSK-3 beta 结合，上调其磷酸化，并增加 β-catenin 及其下游效应子的表达。总的来说，这些发现表明 TNFRSF11B 促进 GC 细胞的侵袭性表型并激活 Wnt/β-catenin 信号传导。因此，TNFRSF11B 具有作为生物标志物的潜力，抑制 TNFRSF11B 表达可能为 GC 患者提供新的治疗靶点。
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 beta-catenin in the nucleus. The expression of beta-catenin and related protein was determined by Western blot. The interaction between TNFRSF11B and GSK3 beta 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 beta-catenin showed positively correlation with TNFRSF11B expression. TNFRSF11B directly combined with GSK-3 beta upregulating its phosphorylation, and increased expression of beta-catenin and its downstream effectors. Collectively, these findings demonstrate that TNFRSF11B promote the aggressive phenotypes of GC cells and activated Wnt/beta-catenin signaling. Accordingly, TNFRSF11B had potential as a biomarker and inhibition of TNFRSF11B expression might offer a new therapeutic target for GC patients.