CLIC3, Chloride intracellular channel 3, is a member of the glutathione-S-transferase (GSTs) superfamily. It is involved in regulating fundamental cellular processes such as chloride ion concentration, cell membrane potential, trans-epithelial transport, cell volume, and apoptotic processes [6]. It has also been implicated in various signaling pathways like the P53 signaling pathway [3].

In cancer research, CLIC3 has been found to play significant roles. In bladder cancer, it interacts with NAT10, inhibits N4-acetylcytidine modification of p21 mRNA, reducing p21 expression and promoting cancer cell proliferation both in vitro and in vivo [1]. High CLIC3 mRNA expression in bladder cancer is associated with adverse clinicopathological factors and poor prognosis, and may be used as a biomarker [3]. In breast cancer, CLIC3 controls the recycling of late endosomal MT1-MMP, dictating invasion and metastasis in ER-negative breast cancer [5]. In pancreatic ductal adenocarcinoma, CLIC3, along with Rab25, promotes integrin recycling from late endosomes/lysosomes, and its expression predicts lymph node metastasis and poor prognosis [8]. In gastric cancer, CLIC3 functions as a Cl-channel in the plasma membrane, and decreased expression is associated with unfavorable prognosis [4]. In salivary gland mucoepidermoid carcinoma, hypomethylation of the CLIC3 promoter and its overexpression are significant events [9]. Also, secreted CLIC3 from cancer and stromal cells promotes angiogenesis and cancer cell invasiveness through its glutathione-dependent oxidoreductase activity [2].

In summary, CLIC3 is crucial in multiple cellular processes and has a profound impact on cancer progression, as demonstrated by various in vivo and in vitro studies. Its role in cancer makes it a potential therapeutic target and biomarker, highlighting the importance of further research on CLIC3 in understanding cancer biology and developing novel treatments. In addition, its association with other diseases like fetal growth restriction, pre-eclampsia [6], and schizophrenia [7] also indicates its wide-ranging biological significance.

References:

1. Shuai, Yujun, Zhang, Hui, Liu, Changhao, Chen, Hebing, Jiang, Guosong. 2024. CLIC3 interacts with NAT10 to inhibit N4-acetylcytidine modification of p21 mRNA and promote bladder cancer progression. In Cell death & disease, 15, 9. doi:10.1038/s41419-023-06373-z. https://pubmed.ncbi.nlm.nih.gov/38182571/

2. Hernandez-Fernaud, Juan R, Ruengeler, Elena, Casazza, Andrea, Norman, Jim C, Zanivan, Sara. 2017. Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity. In Nature communications, 8, 14206. doi:10.1038/ncomms14206. https://pubmed.ncbi.nlm.nih.gov/28198360/

3. Chen, Mei, Zhang, Shufang, Wen, Xiaohong, Cao, Hui, Gao, Yuanhui. 2020. Prognostic value of CLIC3 mRNA overexpression in bladder cancer. In PeerJ, 8, e8348. doi:10.7717/peerj.8348. https://pubmed.ncbi.nlm.nih.gov/31934512/

4. Kawai, Shunsuke, Fujii, Takuto, Shimizu, Takahiro, Sakai, Hideki, Fujii, Tsutomu. 2020. Pathophysiological properties of CLIC3 chloride channel in human gastric cancer cells. In The journal of physiological sciences : JPS, 70, 15. doi:10.1186/s12576-020-00740-7. https://pubmed.ncbi.nlm.nih.gov/32066374/

5. Macpherson, Iain R, Rainero, Elena, Mitchell, Louise E, Timpson, Paul, Norman, Jim C. 2014. CLIC3 controls recycling of late endosomal MT1-MMP and dictates invasion and metastasis in breast cancer. In Journal of cell science, 127, 3893-901. doi:10.1242/jcs.135947. https://pubmed.ncbi.nlm.nih.gov/25015290/

6. Murthi, P, Stevenson, J L, Money, T T, Brennecke, S P, Gude, N M. 2012. Placental CLIC3 is increased in fetal growth restriction and pre-eclampsia affected human pregnancies. In Placenta, 33, 741-4. doi:10.1016/j.placenta.2012.06.011. https://pubmed.ncbi.nlm.nih.gov/22795578/

7. Zhu, Xiaoli, Wang, Chuan-Lan, Yu, Jian-Feng, Tang, Xiaowei, Pan, Bo. 2023. Identification of immune-related biomarkers in peripheral blood of schizophrenia using bioinformatic methods and machine learning algorithms. In Frontiers in cellular neuroscience, 17, 1256184. doi:10.3389/fncel.2023.1256184. https://pubmed.ncbi.nlm.nih.gov/37841288/

8. Dozynkiewicz, Marta A, Jamieson, Nigel B, Macpherson, Iain, Caswell, Patrick T, Norman, Jim C. 2011. Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression. In Developmental cell, 22, 131-45. doi:10.1016/j.devcel.2011.11.008. https://pubmed.ncbi.nlm.nih.gov/22197222/

9. Wang, Zhiming, Ling, Shizhang, Rettig, Eleni, Fakhry, Carole, Ha, Patrick K. 2015. Epigenetic screening of salivary gland mucoepidermoid carcinoma identifies hypomethylation of CLIC3 as a common alteration. In Oral oncology, 51, 1120-5. doi:10.1016/j.oraloncology.2015.09.010. https://pubmed.ncbi.nlm.nih.gov/26490796/