TGFB2 serves as a link between epithelial-mesenchymal transition and tumor mutation burden in gastric cancer.
TGFB2 serves as a link between epithelial-mesenchymal transition and tumor mutation burden in gastric cancer.
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DOI：
10.1016/j.intimp.2020.106532
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发表时间：
2020-05
影响因子：
5.6
通讯作者：
Bowen Yang;Jin Bai;Ruichuan Shi;X. Shao;Yujing Yang;Yue Jin;X. Che;Ye Zhang;X. Qu;Yunpeng Liu;Zhi Li
中科院分区：
文献类型：
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作者：
Bowen Yang;Jin Bai;Ruichuan Shi;X. Shao;Yujing Yang;Yue Jin;X. Che;Ye Zhang;X. Qu;Yunpeng Liu;Zhi Li
免疫检查点阻断（ICB）已成为包括胃癌（GC）在内的各种癌症的重大突破，但临床结果仍然很差。目前，上皮间质转化（EMT）已被报道与肿瘤突变负荷（TMB），这可能会导致缺乏反应ICB。然而，其潜在机制仍不清楚。转化生长因子β（TGF β 2）家族成员被认为是EMT的主要介质，但TGF β 2在GC中如何驱动EMT尚不完全清楚。在本研究中，我们发现TGCA-STAD和四个GEO GC数据集中TGFB 2的过表达与不良预后相关，基因集富集分析显示EMT途径在TGFB 2高表达组中显著富集，而TMB相关途径包括错配修复、碱基切除修复和DNA复制在低表达组中强烈富集。此外，EMT评分分析、WGCNA和功能分析表明，TGFB 2与可能驱动EMT的神经突相关通路共表达。此外，CIBERSORT分析显示，肿瘤浸润免疫细胞如T滤泡辅助细胞可能参与了TGFB 2影响GC中TMB水平的过程。此外，在其他各种癌症中，TGFB 2也与TMB水平以及ICB反应呈负相关。总之，这些结果表明，TGFB 2可以在GC中连接EMT和TMB中发挥重要作用，表明TGFB 2可能是GC的预测性治疗靶点。
Immune checkpoint blockade (ICB) has been a major breakthrough in various cancers including gastric cancer (GC), yet the clinical outcomes remain poor. Currently, epithelial-mesenchymal transition (EMT) has been reported to be associated with tumor mutational burden (TMB), which can cause lack of response to ICB. However, the underlying mechanism remains unknown. Members of the transforming growth factor β (TGFB) family are regarded as the main mediators of EMT, yet how TGFB2 drives EMT in GC is not fully understood. In this study, we found that overexpression of TGFB2 was correlated with poor prognosis in TGCA-STAD and four GEO GC datasets. Gene set enrichment analysis revealed that the EMT pathway was significantly enriched in the high TGFB2 expression group, whilst the TMB-related pathways including mismatch repair, base excision repair, and DNA replication were strongly enriched in the low expression group. Furthermore, EMT score analysis, WGCNA and functional analysis showed that TGFB2 was co-expressed with neurite-related pathways that might drive EMT. Also, CIBERSORT analysis revealed that tumor-infiltrating immune cells like T follicular helper cells might participate in the process of TGFB2 affecting TMB levels in GC. Moreover, in other various cancers, TGFB2 was also negatively correlated with TMB levels as well as ICB response. Overall, these results revealed that TGFB2 could play a vital role in linking EMT and TMB in GC, suggesting that TGFB2 may be a predictive therapeutic target for GC.