Serum exosomal miR‐638 is a prognostic marker of HCC via downregulation of VE‐cadherin and ZO‐1 of endothelial cells

Hepatocellular carcinoma (HCC) is the second leading cause of cancer‐related death. High recurrence rates after curative resection and the lack of specific biomarkers for intrahepatic metastases are major clinical problems. Recently, exosomal microRNAs (miRNAs) have been reported to have a role in the formation of the pre‐metastatic niche and as promising biomarkers in patients with malignancy. Here we aimed to clarify the molecular mechanisms of intrahepatic metastasis and to identify a novel biomarker miRNA in patients with HCC. A highly intrahepatic metastatic cell line (HuH‐7M) was established by in vivo selection. HuH‐7M showed increased proliferative ability and suppression of apoptosis and anoikis. HuH‐7M and the parental cell (HuH‐7P) showed the similar expression of epithelial‐mesenchymal transition markers and cancer stem cell markers. In vivo, mice treated with exosomes derived from HuH‐7M showed increased tumorigenesis of liver metastases. Exosomes from HuH‐7M downregulated endothelial cell expression of vascular endothelial‐cadherin (VE‐cadherin) and zonula occludens‐1 (ZO‐1) in non‐cancerous regions of liver and increased the permeability of FITC‐dextran through the monolayer of endothelial cells. The miRNAs (miR‐638, miR‐663a, miR‐3648, and miR‐4258) could attenuate endothelial junction integrity by inhibiting VE‐cadherin and ZO‐1 expression. In patients with HCC, higher serum exosomal miR‐638 expression was associated with tumor recurrence. In conclusion, the miRNAs secreted from a highly metastatic cancer cell can promote vascular permeability via downregulation of endothelial expression of VE‐cadherin and ZO‐1. Serum exosomal miR‐638 expression holds potential for serving as a significant and independent prognostic marker in HCC. miR‐638, miR‐663a, miR‐3648, and miR‐4258 downregulate VE‐cadherin and ZO‐1 expression in HUVECs.