Li Xiao, Sun Baocun, Zhao Xiulan, An Jindan, Zhang Yanhui, Gu Qiang, Zhao Nan, Wang Yong, Liu Fang
Department Of Pathology, General Hospital Of Tianjin Medical University, Tianjin, 300052, China.
Department Of Pathology, Tianjin Medical University, Tianjin, 300070, China.
J Cancer. 2020 Feb 10;11(9):2560-2571. doi: 10.7150/jca.40558. eCollection 2020.
Vasculogenic mimicry (VM) is linked to vascular invasion of human hepatocellular carcinoma (HCC). BMP4, one BMP family member, is upregulated in several cancers. The purpose of this report is to identify the function of BMP4 in the formation of VM in HCC and the mechanism underling this regulation. In our report, BMP4 up-regulation resulted in an increase in migration, invasion and channel-like structure formation as well as induced epithelial-mesenchymal transition (EMT) process and stem cell-associated proteins OCT4 and SOX2 expression in HCC cells. In addition, The VM-associated proteins, including EphA2, VE-cadherin and MMP2, also could be effectively enhanced by the overexpression of BMP4. Furthermore, according to the TCGA database, higher expression of BMP4 is seen in HCC in contrast to normal liver samples. Immunohistochemistry revealed that BMP4 was positively associated with VM formation, age, histological differentiation, HCC stage, and shorter survival duration. These data demonstrated that BMP4 could promote VM network formation in HCC through induction of stemness in EMT and modulating the EphA2/VE-cadherin/MMP2 signaling pathway.
血管生成拟态（VM）与人类肝细胞癌（HCC）的血管侵袭有关。骨形态发生蛋白4（BMP4）是骨形态发生蛋白家族成员之一，在多种癌症中表达上调。本报告的目的是确定BMP4在HCC中VM形成中的作用及其调控机制。在本报告中，BMP4上调导致HCC细胞的迁移、侵袭和管状结构形成增加，并诱导上皮-间质转化（EMT）过程以及干细胞相关蛋白OCT4和SOX2表达。此外，BMP4过表达还可有效增强包括EphA2、血管内皮钙黏蛋白（VE-cadherin）和基质金属蛋白酶2（MMP2）在内的VM相关蛋白的表达。此外，根据癌症基因组图谱（TCGA）数据库，与正常肝脏样本相比，HCC中BMP4表达更高。免疫组织化学显示，BMP4与VM形成、年龄、组织学分化、HCC分期以及较短的生存时间呈正相关。这些数据表明，BMP4可通过诱导EMT中的干性和调节EphA2/VE-cadherin/MMP2信号通路促进HCC中VM网络的形成。
