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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.

SUBMITTER: Yokota Y

PROVIDER: S-EPMC7935782 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Yokota Yuki Y Noda Takehiro T Okumura Yuichiro Y Kobayashi Shogo S Iwagami Yoshifumi Y Yamada Daisaku D Tomimaru Yoshito Y Akita Hirofumi H Gotoh Kunihito K Takeda Yutaka Y Tanemura Masahiro M Murakami Takashi T Umeshita Koji K Doki Yuichiro Y Eguchi Hidetoshi H

Cancer science 20210129 3

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 b ...[more]

PMID: 33426736

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Project description:RATIONALE:The mechanistic foundation of vascular maturation is still largely unknown. Several human pathologies are characterized by deregulated angiogenesis and unstable blood vessels. Solid tumors, for instance, get their nourishment from newly formed structurally abnormal vessels which present wide and irregular interendothelial junctions. Expression and clustering of the main endothelial-specific adherens junction protein, VEC (vascular endothelial cadherin), upregulate genes with key roles in endothelial differentiation and stability. OBJECTIVE:We aim at understanding the molecular mechanisms through which VEC triggers the expression of a set of genes involved in endothelial differentiation and vascular stabilization. METHODS AND RESULTS:We compared a VEC-null cell line with the same line reconstituted with VEC wild-type cDNA. VEC expression and clustering upregulated endothelial-specific genes with key roles in vascular stabilization including claudin-5, vascular endothelial-protein tyrosine phosphatase (VE-PTP), and von Willebrand factor (vWf). Mechanistically, VEC exerts this effect by inhibiting polycomb protein activity on the specific gene promoters. This is achieved by preventing nuclear translocation of FoxO1 (Forkhead box protein O1) and ?-catenin, which contribute to PRC2 (polycomb repressive complex-2) binding to promoter regions of claudin-5, VE-PTP, and vWf. VEC/?-catenin complex also sequesters a core subunit of PRC2 (Ezh2 [enhancer of zeste homolog 2]) at the cell membrane, preventing its nuclear translocation. Inhibition of Ezh2/VEC association increases Ezh2 recruitment to claudin-5, VE-PTP, and vWf promoters, causing gene downregulation. RNA sequencing comparison of VEC-null and VEC-positive cells suggested a more general role of VEC in activating endothelial genes and triggering a vascular stability-related gene expression program. In pathological angiogenesis of human ovarian carcinomas, reduced VEC expression paralleled decreased levels of claudin-5 and VE-PTP. CONCLUSIONS:These data extend the knowledge of polycomb-mediated regulation of gene expression to endothelial cell differentiation and vessel maturation. The identified mechanism opens novel therapeutic opportunities to modulate endothelial gene expression and induce vascular normalization through pharmacological inhibition of the polycomb-mediated repression system.

Dataset Information

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

Publications

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

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