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Abstract：
Objective: Tetratricopeptide repeat (TRP)-mediated cofactor proteins are involved in a wide range of cancers. TTC36 is little studied member of TRP subfamily. This study aimed to investigate the role of TTC36 in human gastric carcinoma (GC) and explore the potential underlying mechanisms. Methods: The analysis of TTC36 differential expression in GC was conducted using data from TCGA and a human tissue microarray. And effects of TTC36 expression on the prognosis of patients with gastric carcinoma were analyzed using the data from the GEO database. Lentivirus was transfected into the cell lines of AGS and BGC823 to construct overexpression and knocked down TTC36 cell model respectively. The effect of TTC36 expression on the growth, apoptosis and cell cycle of cells was explored in vitro. Downstream molecules were detected by western blotting. GSEA predicted signal pathway and related proteins were then detected. Results: TTC36 expression in human GC tissues was found significantly lower than that in adjacent normal tissues and closely related to clinical prognosis. The overexpression of TTC36 notably inhibited tumor progression, cell cycle G1/S transfer and increased apoptosis in AGS cells. Conversely, the opposite effects were observed when TTC36 was suppressed in BGC823 cells. The expression of cleaved caspase3, Survivin, cyclin D1 and c-Myc were consistent with the phenotype in TTC36 operated GC cell lines. Intriguingly, GSEA analysis predicted Wnt-β-catenin pathway involved in TTC36 induced effects in GC cells, expression of β-catenin and downstream molecules such as TCF4, c-jun and pAKT were found negative related to TTC36 expression in GC cells. Notably, treatment with the Wnt/β-catenin inhibitor XAV939 dramatically attenuated the effects of TTC36 in GC cells. Conclusion: These results signify a critical role for TTC36 as a tumor suppressor in gastric carcinoma via regulating Wnt-β-catenin pathway.
摘要：
目的：四肽重复序列（TRP）介导的辅因子蛋白与多种癌症有关。TTC36是很少研究的TRP亚家族成员。本研究旨在探讨TTC36在胃癌中的作用及潜在机制。方法：使用TCGA和人组织微阵列的数据进行GC中TTC36差异表达的分析。并使用GEO数据库中的数据分析了TTC36表达对胃癌患者预后的影响。将慢病毒分别转染到AGS和BGC823的细胞系中，以构建过表达和敲低TTC36细胞模型。TTC36表达对其生长的影响，细胞凋亡和细胞周期的体外研究。通过蛋白质印迹检测下游分子。然后检测GSEA预测信号通路和相关蛋白。结果：人GC组织中TTC36的表达明显低于癌旁正常组织，与临床预后密切相关。TTC36的过表达显著抑制肿瘤进展，细胞周期G1/S转移和AGS细胞凋亡增加。相反，当在BGC823细胞中抑制TTC36时，观察到相反的作用。caspase3、Survivin的表达,细胞周期蛋白D1和c-Myc与TTC36操作的GC细胞系的表型一致。有趣的是，GSEA分析预测Wnt-β-catenin通路参与TTC36对GC细胞的诱导作用,发现β-catenin和下游分子如TCF4，c-jun和pAKT的表达与GC细胞中TTC36的表达呈负相关。值得注意的是,用Wnt/β-连环蛋白抑制剂XAV939处理显著减弱TC36在GC细胞中的作用。结论：这些结果表明，TTC36通过调节Wnt-β-catenin通路在胃癌中作为肿瘤抑制因子具有重要作用。
