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Inhibition of PCSK9 Attenuates Liver Endothelial Cell Activation Induced by Colorectal Cancer Stem Cells During Liver Metastasis

  • 0Bordeaux Institute of Oncology (BRIC)-UMR1312, University of Bordeaux, 33000 Bordeaux, France.
Cancers +

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June 26, 2025

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June 26, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes liver sinusoidal endothelial cell (LSEC) activation in response to colorectal cancer stem cells (CSCs), driving liver metastasis. Inhibiting PCSK9 may offer a new therapeutic strategy for colorectal cancer liver metastases.

Area Of Science

  • Oncology
  • Cell Biology
  • Molecular Medicine

Background

  • Colorectal cancer (CRC) is a leading cause of cancer mortality, with liver metastasis being a primary driver.
  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) is overexpressed in CRC and implicated in metastatic progression.
  • Liver sinusoidal endothelial cells (LSECs) are crucial components of the liver microenvironment and play a role in metastasis.

Purpose Of The Study

  • To investigate the role of PCSK9 in the liver metastatic niche.
  • To determine the effects of PCSK9 on LSECs in the context of colorectal cancer stem cells (CSCs).
  • To explore PCSK9 as a potential therapeutic target for colorectal cancer liver metastasis.

Main Methods

  • LSECs were stimulated with conditioned media from CRC cells and CSCs.
  • Gene expression profiling of LSECs was performed using RNA sequencing.
  • PCSK9 levels were quantified via qPCR and Western blotting.
  • Immunofluorescent staining assessed PCSK9 expression in liver metastases.
  • Functional assays evaluated LSEC proliferation and migration, with and without PCSK9 inhibition.

Main Results

  • PCSK9 was detected and upregulated in LSECs upon exposure to CSC-conditioned media.
  • PCSK9 expression was confirmed in LSECs within CRC liver metastases.
  • PCSK9 inhibition reduced microRNAs associated with cell migration and proliferation in LSECs.
  • CSC-conditioned media enhanced LSEC proliferation and migration, effects reversed by PCSK9 inhibition.

Conclusions

  • PCSK9 activation of LSECs contributes to a pro-metastatic phenotype in colorectal cancer liver metastasis.
  • Targeting PCSK9 presents a promising therapeutic strategy to combat colorectal cancer liver metastasis.

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