由 C12orf59/NF-κB/CDH11 组成的正反馈环促进胃癌侵袭和转移。

A positive feedback loop consisting of C12orf59/NF-κB/CDH11 promotes gastric cancer invasion and metastasis.

机构信息

The State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, No. 651, Dongfeng Road East, 510060, Guangzhou, Guangdong Province, People's Republic of China.

Department of Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, Guangdong Province, People's Republic of China.

出版信息

J Exp Clin Cancer Res. 2019 Apr 15;38(1):164. doi: 10.1186/s13046-019-1114-2.

DOI:10.1186/s13046-019-1114-2

PMID:30987656

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6463669/

Abstract

BACKGROUND

Metastasis remains the main cause of cancer-related death for gastric cancer (GC) patients, but the mechanisms are poorly understood. Using The Cancer Genome Atlas (TCGA) data base and bioinformatics analyses, we identified C12orf59 might act as a potential oncogenic protein in GC.

METHODS

We investigate the expression pattern and clinical significance of C12orf59 in two independent cohorts of GC samples. In the training cohort, we used the X-tile program software to generate the optimal cutoff value for C12orf59 expression in order to classify patients accurately according to clinical outcome. In the validation cohort, this derived cutoff score was applied to exam the association of C12orf59 expression with survival outcome. A series of in vivo and in vitro assays were then performed to investigate the function of C12orf59 in GC.

RESULTS

C12orf59 was significantly upregulated, and associated with poor survival outcome in two cohorts of GC samples. Gain- and loss of- function studies demonstrated C12orf59 promotes GC cell invasive and metastatic capacity both in vitro and in vivo, and induces epithelial-mesenchymal transition and angiogenesis. Mechanically, C12orf59 exerts oncogenic functions by up-regulating CDH11 expression via NF-κB signaling. Interesting, CDH11 could in turn promote NF-κB bind to C12orf59's promoter and form a positive feedback loop to sustain the metastatic ability of GC cells. Additionally, downregulation of miR-654-5p is another important mechanism for C12orf59 overexpression in GC.

CONCLUSION

Our finding suggested the newly identified C12orf59/NF-κB/CDH11 feedback loop may represent a new strategy for GC treatment.

摘要

背景

转移仍然是胃癌（GC）患者癌症相关死亡的主要原因，但机制尚不清楚。我们使用癌症基因组图谱（TCGA）数据库和生物信息学分析，鉴定 C12orf59 可能在 GC 中作为一种潜在的致癌蛋白。

方法

我们研究了 C12orf59 在两个独立的 GC 样本队列中的表达模式和临床意义。在训练队列中，我们使用 X-tile 程序软件生成 C12orf59 表达的最佳截断值，以便根据临床结果准确地对患者进行分类。在验证队列中，应用该衍生的截断评分来检查 C12orf59 表达与生存结果的相关性。然后进行了一系列体内和体外实验来研究 C12orf59 在 GC 中的功能。

结果

C12orf59 在两个 GC 样本队列中均显著上调，并与不良生存结局相关。增益和缺失功能研究表明，C12orf59 促进 GC 细胞的侵袭和转移能力，无论是在体外还是体内，并诱导上皮-间充质转化和血管生成。机制上，C12orf59 通过 NF-κB 信号上调 CDH11 表达发挥致癌作用。有趣的是，CDH11 可以反过来促进 NF-κB 与 C12orf59 的启动子结合，并形成正反馈环以维持 GC 细胞的转移能力。此外，miR-654-5p 的下调是 C12orf59 在 GC 中过表达的另一个重要机制。