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

Abstract

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.

• Authors: Yuki Yokota, Takehiro Noda, Yuichiro Okumura, Shogo Kobayashi, Yoshifumi Iwagami, Daisaku Yamada, Yoshito Tomimaru, Hirofumi Akita, Kunihito Gotoh, Yutaka Takeda, Masahiro Tanemura, Takashi Murakami, Koji Umeshita, Yuichiro Doki, Hidetoshi Eguchi
• Journal: Cancer science (Cancer Sci) Vol. 112 Issue 3 Pg. 1275-1288 (Mar 2021) ISSN: 1349-7006 [Electronic] England
• PMID: 33426736 (Publication Type: Journal Article, Observational Study)
• Copyright: © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antigens, CD
• Biomarkers, Tumor
• Cadherins
• MIRN638 microRNA, human
• MicroRNAs
• TJP1 protein, human
• Zonula Occludens-1 Protein
• cadherin 5

Topics

• Aged
• Aged, 80 and over
• Animals
• Antigens, CD (genetics)
• Biomarkers, Tumor (blood, metabolism)
• Cadherins (genetics)
• Carcinoma, Hepatocellular (blood, genetics, mortality, surgery)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Down-Regulation
• Endothelial Cells (pathology)
• Epithelial-Mesenchymal Transition (genetics)
• Exosomes (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Hepatectomy
• Human Umbilical Vein Endothelial Cells
• Humans
• Liver (cytology, pathology, surgery)
• Liver Neoplasms (blood, genetics, mortality, surgery)
• Male
• Mice
• MicroRNAs (metabolism)
• Middle Aged
• Neoplasm Recurrence, Local (diagnosis, genetics, prevention & control)
• Preoperative Period
• Zonula Occludens-1 Protein (genetics)