CLIC2 regulates immunosuppression and macrophage differentiation in genomically stable gastric cancer

• Published in: Biology direct Vol. 20; no. 1; pp. 89 - 16
• Main Authors: Longo, Viviana, Mazzone, Pellegrino, Calice, Giovanni, Zoppoli, Pietro, Di Paola, Giuseppina, Cesta, Giuseppe, Luongo, Margherita, Sabato, Claudia, Russi, Sabino, Laurino, Simona, Notarangelo, Tiziana, Patitucci, Giuseppe, Balzamo, Chiara, Lucci, Valeria, Amendola, Elena, Amodio, Giuseppina, Remondelli, Paolo, Pagliara, Valentina, Milone, Maria Rita, Guadagno, Roberta, De Stefano, Cristofaro, De Vita, Ferdinando, Falco, Geppino, Albano, Francesco
• Format: Journal Article
• Language: English
• Published: London BioMed Central 22.07.2025; BioMed Central Ltd; BMC
• Subjects: Analysis; Anopheles; Biomedical and Life Sciences; Brain cancer; Cancer; Care and treatment; CD11b antigen; CD11c antigen; CD80 antigen; CD86 antigen; Cell differentiation; Cell Differentiation - genetics; Cells; Chloride channels; Chloride Channels - genetics; Chloride Channels - metabolism; Clic2; Cloning; Development and progression; Diagnosis; Differentiation; Disease; Endothelial cells; Endothelium; Fibroblasts; Gastric cancer; Gastric microenvironment; Gene expression; Genetic aspects; Genomes; Health aspects; Humans; Immunosuppression; Immunotherapy; Life Sciences; Localization; Macrophages; Macrophages - metabolism; Medical prognosis; Microenvironments; Monocytes; Osteoprotegerin; Patient outcomes; Phosphatases; Phosphorylation; Proteins; SHP-1 protein; Signal transduction; Stat3 protein; Stomach cancer; Stomach Neoplasms - genetics; Stomach Neoplasms - immunology; Stomach Neoplasms - metabolism; Tumor microenvironment; Tumors; Italy; United States; United Kingdom; California; Signaling; Tumor microenvironment; Gastric microenvironment; Macrophages; Differentiation; Gastric cancer; Clic2
• ISSN: 1745-6150; 1745-6150
• DOI: 10.1186/s13062-025-00666-3

Chloride intracellular channels (CLICs) are a family of six evolutionarily conserved proteins with diverse functions. Previously, we identified CLIC2, as the fifth-ranked master regulator associated with diffuse-type gastric cancer (dGC) showing increased expression in tumors. Here we used bulk, as well as single cell sequencing datasets of dGC, to demonstrate for the first time a direct association of CLIC2 with the microsatellite stable GC and, furthermore, the expression of CLIC2 in macrophages (MCs), and endothelial cells (ECs) populating gastric tissue. We generated CLIC2 knock-out THP-1 monocytic cells (THP-1CLIC2_KO) determining that while CLIC2 deletion had no observable effect on monocytes, THP-1CLIC2_KO macrophages exhibited significant morphological changes, including increased membrane protrusions, and upregulated expression of CD11b, CD11c, CD80, and CD86 markers. Furthermore, cytokine secretion profiling of THP-1CLIC2_KO differentiated cells revealed elevated secretion of CCL8, alongside reduced secretion of IL-1β, IL-6, and osteoprotegerin (OPG). Additionally, we observed increased phosphorylation of Shp1 phosphatase with the concomitant absence of Stat3 phosphorylation, which impaired downstream signaling, in line with the evidence that Clic2 interacts with both Shp1 and Stat3. Based on these findings, we suggest that CLIC2 plays a pivotal role in regulating monocyte-to-macrophage differentiation by modulating the Stat3 signaling pathway, thus enhancing gastric cancer progression by establishing a tumor-permissive microenvironment.