Identification of Subtype-Specific Three-Gene Signature for Prognostic Prediction in Diffuse Type Gastric Cancer
Identification of Subtype-Specific Three-Gene Signature for Prognostic Prediction in Diffuse Type Gastric Cancer
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DOI：
10.3389/fonc.2019.01243
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发表时间：
2019-11-12
影响因子：
4.7
通讯作者：
Che, Xiaofang
中科院分区：
文献类型：
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作者：
Bao, Bowen;Zheng, Chunlei;Che, Xiaofang
胃癌（GC）具有较高的异质性，根据Lauren分类系统主要分为肠型和弥漫型。尽管这两种类型之间存在许多差异，但尚未进行用于评估 GC 预后的 Lauren 亚型特异性多基因特征的研究，并且其不良预后的分子机制仍然难以捉摸。因此，本研究旨在探索亚型特异性多基因特征，用于劳伦分类不同亚型的预后预测。结合最小绝对收缩和选择算子 (LASSO) 算法和 Akaike 信息准则 (AIC)，使用 GSE62254 数据集在弥漫型 GC 中成功建立了 3 基因亚型特异性预后特征。根据 3 基因特征计算风险评分 (RS) 后，建立列线图模型来预测弥漫型 GC 的 1 年、3 年和 5 年总生存率。此外，弥漫型GC的预后预测列线图模型也被证明对于GSE1549数据集的验证和基于基因表达综合（GEO）的荟萃分析是有效的。在RS与临床病理特征之间的相关性分析中，发现RS和3基因标签中的两个基因（EMCN和COL4A5）与腹膜转移呈正相关。此外，EMCN和COL4A5，而不是CCL11，被证明能够增强MKN45和NUGC4细胞对腹膜间皮细胞系HMR-SV5的粘附能力。最终证明COL4A5通过激活Wnt信号通路促进腹膜转移，而FAK-AKT/ERK/STAT3信号通路激活介导的整合素家族基因上调参与了EMCN的腹膜转移促进功能。综上所述，我们的研究确定了弥漫型GC中亚型特异性的3基因特征，这可以有效预测患者的OS，并可能解释其预后不良的分子机制。
Gastric cancer (GC), with high heterogeneity, can be mainly classified into intestinal type and diffuse type according to the Lauren classification system. Although a number of differences were reported between these two types, no study on the Lauren subtype-specific multi-gene signature for evaluation of GC prognosis has been conducted, and the molecular mechanism underlying its poor prognosis has still remained elusive. Therefore, this study aimed to explore subtype-specific multi-gene signature for prognostic prediction in different subtypes of Lauren classification. With combination of the least absolute shrinkage and selection operator (LASSO) algorithm and the Akaike information criterion (AIC), the 3-gene subtype-specific prognostic signature was successfully established in diffuse type GC using GSE62254 dataset. Following the calculation of risk score (RS) based on 3-gene signature, the nomogram models were established to predict 1-, 3-, and 5-year overall survival in diffuse type GC. Moreover, the prognostic predictive nomogram model of diffuse type GC was also proved to be effective for validation of GSE1549 dataset and by a Gene Expression Omnibus (GEO)-based meta-analysis. In the analysis of the correlation between RS and clinical-pathological characteristics, RS and two genes of the 3-gene signature (EMCN and COL4A5) were found to be positively correlated with peritoneal metastasis. Furthermore, EMCN and COL4A5, rather than CCL11, were proved to be able to enhance the adhesion ability of MKN45 and NUGC4 cells to peritoneal mesothelial cell line HMR-SV5. Eventually, it was proved that COL4A5 promoted peritoneal metastasis by activating Wnt signaling pathway, whereas the upregulation of integrin family genes mediated by FAK-AKT/ERK/STAT3 signaling pathway activation is involved in peritoneal metastasis promotion function of EMCN. Taken together, our study identified the subtype-specific 3-gene signature in diffuse type GC, which could effectively predict the patients' OS and might explain the molecular mechanisms in presence of its poor prognosis.