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Chloride intracellular channel protein 2 in cancer and non-cancer human tissues: relationship with tight junctions

Yoshitomo Ueno1, Saya Ozaki2, Akihiro Umakoshi3

  • 1a Department of Hepato-biliary Pancreatic Surgery and Breast Surgery, Graduate School of Medicine , Ehime University , Toon , Ehime , Japan.

Tissue Barriers
|April 2, 2019
PubMed

Insights

Chloride intracellular channel protein 2 (CLIC2) is predominantly found in non-cancerous tissues, supporting tight junction integrity. Loss of CLIC2 in cancer vasculature correlates with increased cancer cell transmigration, suggesting a role in metastasis.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Chloride intracellular channel protein 2 (CLIC2) is a multifunctional protein within the CLIC family.
  • CLIC2 is the least understood member of the CLIC protein family.
  • CLIC proteins are implicated in cellular functions beyond chloride channel activity.

Purpose of the Study:

  • To investigate the expression and localization of CLIC2 in human hepatocellular carcinoma (HCC), metastatic colorectal cancer (CRC) in the liver, and primary CRC.
  • To determine the association of CLIC2 with vascular endothelial cells and tight junction proteins in cancerous and non-cancerous tissues.
  • To evaluate the functional role of CLIC2 in cancer cell transmigration.

Main Methods:

  • Analysis of CLIC2 mRNA and protein expression in human liver and colorectal cancer tissues.
  • Immunohistochemical staining for CLIC2 and tight junction proteins (claudins 1 and 5, occludin, ZO-1) in endothelial cells.
  • Isolation and molecular analysis of CD31+/CD45- endothelial cells from tumor and adjacent non-tumor tissues.
  • In vitro transmigration assays using human umbilical vein endothelial cells (HUVECs) with CLIC2 knockdown.

Main Results:

  • CLIC2 mRNA was significantly expressed in human tissues, predominantly in non-cancerous tissues surrounding tumors.
  • Low CLIC2 expression was observed in fibrotic/dysfunctional non-cancerous liver tissues and advanced HCC.
  • Non-cancerous endothelial cells expressed CLIC2 and tight junction proteins; cancer-associated vasculature showed significantly reduced expression of these molecules.
  • CLIC2 knockdown in HUVECs facilitated cancer cell transmigration across the endothelial monolayer.

Conclusions:

  • CLIC2 expression is reduced in cancerous tissues and associated vasculature.
  • CLIC2 plays a role in maintaining tight junction integrity in endothelial cells.
  • The absence of CLIC2 and tight junctions in cancer vasculature may promote cancer cell intravasation and hematogenous metastasis.
Keywords:
MetastasisZO-1claudin 1colorectal cancerhepatocellular carcinomalymphatic vessel

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