CLIC1, or Chloride intracellular channel 1, can exist as a monomeric soluble or non-covalent dimeric protein capable of forming an ion channel. It plays diverse roles in cell cycle progression, cell volume regulation, and is involved in multiple cellular processes such as proliferation, invasion, migration, and angiogenesis [1]. It is associated with pathways like Wnt/β-catenin/TCF4, ROS/HIF1α, and Nrf2/HO-1, and is of great biological importance, especially in cancer biology and some inflammatory and metabolic diseases [2,6]. Genetic models are valuable for studying its functions.

In cancer, CLIC1 has been widely studied. In glioblastoma, it facilitates the G1/S phase transition and regulates glioma stem-like cells. Knockdown of CLIC1 in glioma cells led to apoptosis and attenuated cell motility [1,4]. In pancreatic cancer, elevated CLIC1, induced by matrix stiffness, promotes glycolytic metabolism and tumor proliferation [2]. In hepatocellular carcinoma, CLIC1 drives angiogenesis by modulating VEGFA, and knockdown of CLIC1 in Huh7 cells restrained xenograft tumor growth [3]. In esophageal cancer, KCTD4 binds to CLIC1, disrupts its dimerization, increases intracellular Ca2+ levels, and promotes metastasis, and a compound targeting the KCTD4-CLIC1 interaction suppresses cancer metastasis [7]. In oral squamous cell carcinoma, patients with nodal metastases had higher CLIC1 plasma concentration levels [5]. In addition, in obesity mouse models, Clic1 knockout mice ate less and had lower body weight, and pharmacological inhibition of Clic1 also reduced food intake and promoted weight loss [8].

In conclusion, CLIC1 is a multifunctional protein involved in various biological processes. Model-based research, especially through gene knockout in mouse models, has revealed its crucial role in cancer progression, angiogenesis, and obesity-related food intake regulation. These findings provide potential therapeutic targets for treating cancer and obesity.

References:

1. Randhawa, Kamaldeep, Jahani-Asl, Arezu. 2023. CLIC1 regulation of cancer stem cells in glioblastoma. In Current topics in membranes, 92, 99-123. doi:10.1016/bs.ctm.2023.09.004. https://pubmed.ncbi.nlm.nih.gov/38007271/

2. Zheng, Jia-Hao, Zhu, Yu-Heng, Yang, Jian, Sun, Yong-Wei, Liu, De-Jun. 2024. A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer. In Cell reports, 43, 114633. doi:10.1016/j.celrep.2024.114633. https://pubmed.ncbi.nlm.nih.gov/39154343/

3. Wei, Xuyong, Pan, Binhua, Yang, Mengfan, Lin, Hanchao, Xu, Xiao. . CLIC1 Drives Angiogenesis in Hepatocellular Carcinoma by Modulating VEGFA. In Technology in cancer research & treatment, 21, 15330338221106820. doi:10.1177/15330338221106820. https://pubmed.ncbi.nlm.nih.gov/35722791/

4. Wang, Chengcheng, He, Zheng. 2023. Multi-omics analysis reveals CLIC1 as a therapeutic vulnerability of gliomas. In Frontiers in pharmacology, 14, 1279370. doi:10.3389/fphar.2023.1279370. https://pubmed.ncbi.nlm.nih.gov/38027011/

5. Wojtera, Bartosz Paweł, Sobecka, Agnieszka, Szewczyk, Mateusz, Suchorska, Wiktoria Maria, Golusiński, Wojciech. . CLIC1 plasma concentration is associated with lymph node metastases in oral squamous cell carcinoma. In Advances in clinical and experimental medicine : official organ Wroclaw Medical University, 32, 341-347. doi:10.17219/acem/154621. https://pubmed.ncbi.nlm.nih.gov/36251793/

6. Lu, Dezhao, Le, Yifei, Ding, Jiali, Mao, Wei, Zhu, Ji. 2021. CLIC1 Inhibition Protects Against Cellular Senescence and Endothelial Dysfunction Via the Nrf2/HO-1 Pathway. In Cell biochemistry and biophysics, 79, 239-252. doi:10.1007/s12013-020-00959-6. https://pubmed.ncbi.nlm.nih.gov/33432550/

7. Zheng, Cancan, Yu, Xiaomei, Xu, Taoyang, Liu, Jinbao, Xu, Wen Wen. 2023. KCTD4 interacts with CLIC1 to disrupt calcium homeostasis and promote metastasis in esophageal cancer. In Acta pharmaceutica Sinica. B, 13, 4217-4233. doi:10.1016/j.apsb.2023.07.013. https://pubmed.ncbi.nlm.nih.gov/37799381/

8. Zapata, Rizaldy C, Zhang, Dinghong, Yoon, Dongmin, Petrascheck, Michael, Osborn, Olivia. 2023. Targeting Clic1 for the treatment of obesity: A novel therapeutic strategy to reduce food intake and body weight. In Molecular metabolism, 76, 101794. doi:10.1016/j.molmet.2023.101794. https://pubmed.ncbi.nlm.nih.gov/37604246/