Chloride Intracellular Channel 1 (CLIC1) as a Prospective Prognostic Biomarker in Pan-cancer: An Integrative Immunoassay and Clinical Value

Abstract

Background: The chloride intracellular channel 1 (CLIC1) plays a pivotal role in the progression of various cancers as a significant anion channel within the human body. With the rising global cancer incidence, this study aims to elucidate the regulatory mechanisms of CLIC1 to prognosis, the tumor immune microenvironment, and immunotherapy. Methods: We acquired expression matrices and corresponding clinicopathological data for pan-cancer from The Cancer Genome Atlas (TCGA) and UCSC Xena databases. To thoroughly investigate the significance of CLIC1 in pan-cancer, we conducted analyses encompassing genetic information, mutations, and the distribution of CLIC1. Subsequently, we validated differential expression of CLIC1 through experimental methods. Prognostic evaluation was performed using univariate cyclooxygenase (COX) regression, Kaplan-Meier curves, and two primary algorithms. Employing the median CLIC1 expression level as a grouping criterion, we explored biological pathways associated with CLIC1 expression, conducted single-cell transcriptome sequencing, examined immune-infiltrating cells, and investigated immunotherapy. Additionally, we utilized the Connectivity Map (CAMP) to identify potential drugs targeting CLIC1. Results: CLIC1 is overexpressed in a majority of tumors, with specific validation in stomach and thyroid cancers. Notably, a significant correlation between CLIC1 and immune checkpoints, tumor mutational burden, and high-frequency microsatellite stability was observed in certain patients (p < 0.001), indicating potential for CLIC1 in immunotherapy. Moreover, CLIC1 serves as a significant predictor of poor prognosis across various malignant tumors, impacting overall survival, disease-specific survival, disease-free interval, and progression-free interval. Based on CLIC1s expression profile, it was found to be prominently expressed in immunometabolic and biosynthetic pathways. Furthermore, high expression levels of CLIC1 were identified in monocytes, macrophages, and malignant cells, suggesting its potential as a specific marker for these cell types. Notably, a strong correlation was observed between CLIC1 expression levels and immune cell infiltration (p < 0.001). Lastly, a drug database screened for small-molecule drugs related to CLIC1, highlighting potential anticancer applications. Conclusion: This study represents the inaugural demonstration of CLIC1 as a prognostic factor across numerous cancers. Furthermore, it elucidates CLIC1s regulatory role in biological pathways, single-cell landscapes, and the tumor immune microenvironment within pan-cancer contexts. Hence, CLIC1 emerges as a potential biomarker for cancer immunotherapy.