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

Abstract

2019) Chloride intracellular channel protein 2 in cancer and noncancer human tissues: relationship with tight junctions, Tissue Barriers, 7:1, 1593775, ABSTRACT Chloride intracellular channel protein 2 (CLIC2) belongs to the CLIC family of conserved metazoan proteins. Although CLICs have been identified as chloride channels, they are currently considered multifunctional proteins. CLIC2 is the least studied family member. We investigated CLIC2 expression and localization in human hepatocellular carcinoma, metastatic colorectal cancer in the liver, and colorectal cancer. Significant expression of mRNAs encoding CLIC1, 2, 4, and 5 were found in the human tissues, but only CLIC2 was predominantly expressed in non-cancer tissues surrounding cancer masses. Fibrotic or dysfunctional (aspartate aminotransferase ≥40) non-cancer liver tissues and advanced stage HCC tissues expressed low levels of CLIC2. Endothelial cells lining blood vessels but not lymphatic vessels in non-cancer tissues expressed CLIC2 as well as high levels of the tight junction proteins claudins 1 and 5, occludin, and ZO-1. Most endothelial cells in blood vessels in cancer tissues had very low expressions of CLIC2 and tight junction proteins. CD31 + /CD45 − endothelial cells isolated from non-cancer tissues expressed mRNAs encoding CLIC2, claudin 1, occludin and ZO-1, while similar cell fractions from cancer tissues had very low expressions of these molecules. Knockdown of CLIC2 expression in human umbilical vein endothelial cells (HUVECs) allowed human cancer cells to transmigrate through a HUVEC monolayer. These results suggest that CLIC2 may be involved in the formation and/or maintenance of tight junctions and that cancer tissue vasculature lacks CLIC2 and tight junctions, which allows the intravasation of cancer cells necessary for hematogenous metastasis. ARTICLE HISTORY

Int22h1/Int22h2 ‐mediated Xq28 duplication syndrome: de novo duplications, prenatal diagnoses, and additional phenotypic features

“…CLIC2 , the other locus involved in the duplication and also speculated to contribute to the syndrome's manifestations, has been shown to be under‐expressed in hepatocellular carcinoma and colorectal adenocarcinoma, with its expression levels paralleling those of tight junctions. This suggested a possible role for CLIC2 in maintaining cell–cell adhesion and preventing hematogenous dissemination of tumor cells (Ueno et al, 2019). However, it is unclear whether an increase in gene dosage of CLIC2 as occurs in the syndrome would have similar effects in promoting oncogenesis.…”

Intracellular Chloride Channels: Novel Biomarkers in Diseases

“…Recently, CLIC2 was found in endothelial cells in blood vessels, but not lymphatic vessels, in non-cancerous tissues, and its expression is significantly lower when compared to endothelial cells of blood vessels in cancerous tissues. Ablation of CLIC2 in human umbilical vein endothelial cells (HUVECs) compromised the integrity of the vessels and allowed human cancer cells to transmigrate through a HUVEC monolayer (Ueno et al, 2019). In addition to CLIC2, CLIC1, and CLIC4 are also known to be present in endothelial cells (Suh et al, 2005b;Money et al, 2007;Tung and Kitajewski, 2010;Wegner et al, 2010), and CLIC5 is present in placental as well as glomerular endothelial cells (Money et al, 2007;Wegner et al, 2010).…”

“…CLIC2 is not reported as a cancer gene in the network of cancer genes' (NCG 6.0) collection of sources of known cancer genes and 273 cancer mutation screenings (Repana et al, 2019). However, recently it was shown that CLIC2 is highly expressed in non-cancerous cells surrounding cancer masses (Ueno et al, 2019). Expression of CLIC2 and other tight junction proteins such as claudins 1 and 5, occludin and ZO-1 were significantly higher in non-cancer cells as compared to human hepatocellular carcinoma.…”

“…CLIC2 was also detected in type B1 and B2 thymomas . In human hepatocellular carcinoma and colorectal cancer cells, CLIC2 was shown to be important in forming tight junctions in the cancer vasculature and could be playing a role in preventing metastasis (Ueno et al, 2019). However, while there is a lack of extensive studies on CLIC2 in animal models, it is differentially associated with patient survival in various cancers as shown in K-M plots (Figure 2B).…”

Analysis of Differentially Expressed Genes in a Chinese Cohort of Esophageal Squamous Cell Carcinoma

“…From the biological perspective, the chloride intracellular channel (CLIC) family represented by CLIC1-6 constitutes a subgroup of the glutathione-Stransferase (GST) superfamily [31][32][33]. Ion channels play important roles in the development of cancer and their expression is known to be altered in cancer cells [12,34].…”