Department of General Surgery, The First Affiliated Hospital, Sun Yat- sen University, Guangzhou 510080, PR China.
Department of Hepatic Surgery, The First Affiliated Hospital, Sun Yat- sen University, Guangzhou 510080, PR China; Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat- sen University, Guangzhou 510630, PR China.
EBioMedicine. 2019 Aug;46:105-118. doi: 10.1016/j.ebiom.2019.07.002. Epub 2019 Jul 16.
Epithelial-mesenchymal transition (EMT) is critical for cancer cell metastasis. Recently, EMT was reported to be associated with the inflammatory tumour microenvironment and, therefore, might be a predictive biomarker for immune checkpoint blockade agents. However, the underlying mechanism is still unclear.
Patient survival data for our HCC cohort, TCGA and GEO datasets were determined by Kaplan-Meier analysis. The functional roles of ELMO1 in HCC were demonstrated by a series of in vitro and in vivo experiments. Gene microarray analysis was used to demonstrate potential mechanisms of ELMO1. Data retrieved from the TCGA datasets were used to determine the relationships of ELMO1, EMT and TMB.
Here, we report an indispensable role for ELMO1 in linking EMT with tumour mutation burden (TMB), which is a promising biomarker for the immune checkpoint blockade agent response. Upregulated ELMO1 expression is associated with a poor prognosis in hepatocellular carcinoma (HCC), as well as increased cell growth, invasion, migration, angiogenesis and EMT in vitro and in vivo. Mechanistically, we provide evidence that ELMO1 regulates SOX10 expression and induces EMT through PI3K/Akt signalling. Moreover, ELMO1 is negatively associated with TMB, indicating a negative relationship between EMT and TMB.
ELMO1 serves as a link between EMT and TMB, providing a mechanistic basis for the further development of ELMO1 as a therapeutic target against HCC and potentially a promising biomarker of the immune checkpoint blockade agent response. FUND: National Natural Science Foundation of China; Natural Science Foundation of Guangdong Province; Young Teacher Training Program of Sun Yat-sen University; Science and Technology Plan of Guangdong Province; Special Support Program of Guangdong Province, Science and Technology Innovation Youth Talent Support Program; the Pearl River Science and Technology New Talent of Guangzhou City; Medical Scientific Research Foundation of Guangdong Province.
上皮-间充质转化（EMT）对于癌细胞转移至关重要。最近，EMT 与炎症肿瘤微环境相关，并因此可能成为免疫检查点阻断剂的预测生物标志物。然而，其潜在机制尚不清楚。
通过 Kaplan-Meier 分析确定了我们的 HCC 队列、TCGA 和 GEO 数据集的患者生存数据。通过一系列体外和体内实验证明了 ELMO1 在 HCC 中的功能作用。基因微阵列分析用于证明 ELMO1 的潜在机制。从 TCGA 数据集中检索的数据用于确定 ELMO1、EMT 和 TMB 的关系。
在这里，我们报告了 ELMO1 在将 EMT 与肿瘤突变负担（TMB）联系起来方面的不可或缺的作用，TMB 是免疫检查点阻断剂反应的有前途的生物标志物。上调的 ELMO1 表达与肝细胞癌（HCC）的不良预后以及体外和体内的细胞生长、侵袭、迁移、血管生成和 EMT 增加相关。在机制上，我们提供了证据表明 ELMO1 通过 PI3K/Akt 信号通路调节 SOX10 表达并诱导 EMT。此外，ELMO1 与 TMB 呈负相关，表明 EMT 与 TMB 之间存在负相关。
ELMO1 作为 EMT 和 TMB 之间的联系，为进一步将 ELMO1 作为治疗 HCC 的靶点以及免疫检查点阻断剂反应的有前途的生物标志物提供了机制基础。
国家自然科学基金；广东省自然科学基金；中山大学青年教师培育项目；广东省科技计划项目；广东省特支计划科技创新青年拔尖人才项目；广州市珠江科技新星专项；广东省医学科学研究基金。
