J Cancer 2020; 11(9):2560-2571. doi:10.7150/jca.40558

Research Paper

Function of BMP4 in the Formation of Vasculogenic Mimicry in Hepatocellular Carcinoma

Xiao Li1,2, Baocun Sun1,2✉, Xiulan Zhao1,2, Jindan An2,3, Yanhui Zhang3, Qiang Gu1,2, Nan Zhao1,2, Yong Wang3, Fang Liu1,2

1. Department Of Pathology, General Hospital Of Tianjin Medical University, Tianjin, 300052, China
2. Department Of Pathology, Tianjin Medical University, Tianjin, 300070, China
3. Department of Pathology, Cancer Hospital of Tianjin Medical University, Tianjin, 300060, China

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Citation:
Li X, Sun B, Zhao X, An J, Zhang Y, Gu Q, Zhao N, Wang Y, Liu F. Function of BMP4 in the Formation of Vasculogenic Mimicry in Hepatocellular Carcinoma. J Cancer 2020; 11(9):2560-2571. doi:10.7150/jca.40558. Available from http://www.jcancer.org/v11p2560.htm

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Abstract

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.

Keywords: Bone morphogenetic protein 4, hepatocellular carcinoma, vasculogenic mimicry, epithelial-mesenchymal transition, stemness