CLIC1 and CLIC4 complement CA125 as a diagnostic biomarker panel for all subtypes of epithelial ovarian cancer

Abstract

New plasma and tissue biomarkers of epithelial ovarian cancer (EOC) could improve early diagnosis and post-diagnosis clinical management. Here we investigated tissue staining and tissue secretion of CLIC1 and CLIC4 across EOC subtypes. CLIC1 and CLIC4 are two promising biomarkers we previously showed were elevated in EOC patient sera. Individually, CLIC1 or CLIC4 stained larger percentages of malignant tumors across all EOC subtypes compared with CA125, particularly early stage and mucinous tumors. CLIC4 also stained benign tumors but staining was limited to nuclei; whereas malignant tumors showed diffuse cellular staining of stromal and tumor cells. Both proteins were shed by all EOC subtypes tumors in short term organ culture at more consistent levels than CA125, supporting their potential as pan-subtype serum and tissue biomarkers. Elevated CLIC4 expression, but not CLIC1 expression, was a negative indicator of patient survival, and CLIC4 knockdown in cultured cells decreased cell proliferation and migration indicating a potential role in tumor progression. These results suggest CLIC1 and CLIC4 are promising serum and tissue biomarkers as well as potential therapeutic targets for all EOC subtypes. This justifies development of high throughput serum/plasma biomarker assays to evaluate utility of a biomarker panel consisting of CLIC1, CLIC4 and CA125.

Intracellular Chloride Ion Channel Protein-1 Expression in Clear Cell Renal Cell Carcinoma

“…Recently, indeed, Thuringer et al have reported this very crosstalk between glioblastoma cells and endothelial cells that is mediated by CLIC1 released through extracellular vesicles by tumor cells and captured by endothelial cells, which are induced to sprout and form tubes in 3D matrices (34). CLIC1 has already been reported as a potential biomarker for some malignant tumors (6,10,16) and a potential therapeutic target for new treatments in cancer. Its expression in both tumor and endothelial cells may pave the way for the development of future anti-CLIC1 therapy, able to target both tumor and its associated vessels.…”

“…CLIC1 is known as "sensor and effector" of different cellular processes involving the overproduction of reactive oxygen species (ROS) in several benign (28,29) and malignant conditions (10,11). Among malignant tumors, renal cell carcinomas are well known as being highly ROS producing tumors and this is strongly correlated with high tumor grade, advance stage and metastatic behaviour (30).…”

“…Recently, Barbieri et al reported that CLIC1 inhibition induces glioblastoma growth inhibition, mainly by acting on CLIC1-rich glioblastoma stem cells, decreasing their proliferation and subsequently tumor progression (8). Although CLIC1 expression in cancer stem cells (CSC) has been certified only for glioblastoma (7,8), indirect evidence suggests that CLIC1 is also expressed in tumor stem cells from other aggressive malignancies, such as pancreatic (9), ovarian (10) and esophageal cancer (11).…”

Intracellular Chloride Channels: Novel Biomarkers in Diseases

“…CLIC1 is a biomarker for ovarian cancers holding prognostic value (Yu W. et al, 2018). Along with CLIC4, CLIC1 is a promising biomarker for epithelial ovarian cancer where its expression predicts patient survival (Singha et al, 2018). CLIC1 is shown to regulate the redox-sensitivity of ovarian cancer cells and is predicted to be a potential marker for lymphoblastic leukemia (Qu et al, 2016;Dehghan-Nayeri et al, 2017;Singha et al, 2018).…”

“…Along with CLIC4, CLIC1 is a promising biomarker for epithelial ovarian cancer where its expression predicts patient survival (Singha et al, 2018). CLIC1 is shown to regulate the redox-sensitivity of ovarian cancer cells and is predicted to be a potential marker for lymphoblastic leukemia (Qu et al, 2016;Dehghan-Nayeri et al, 2017;Singha et al, 2018). Modulation of CLIC1 expression by micro RNA, hsa-mir-372 predicts the poor prognosis of patients affected with gall bladder cancers (Zhou et al, 2017) and is important for the migration and invasion of gall bladder cancer cells (He et al, 2018).…”