Clca2, short for Calcium-activated chloride channel A2, is a transmembrane protein with multiple functions. It is involved in regulating calcium-activated chloride channel (CaCC) currents, and has been associated with pathways like Wnt/β-catenin, ERK/JNK/p38-MAPK, and is regulated by p53 family proteins. It plays a crucial role in processes such as cell proliferation, migration, invasion, and epithelial-to-mesenchymal transition (EMT), and is important in maintaining cellular homeostasis and preventing premature senescence [1-10].

In cervical cancer, knockdown of Clca2 by small interfering RNA suppressed tumor cell proliferation and migration, and Clca2 was found to be involved in the Wnt/β-catenin signaling pathway. Overexpression of Clca2 inhibited the proliferation, migration, invasion, and promoted apoptosis of cervical cancer cells, and it inhibited EMT through the p38 / JNK / ERK pathway [1,2]. In triple-negative breast cancer, high Clca2 expression was associated with a higher risk of death among African American women [6]. In breast cancer, the absence of Clca2 expression in several tumours and cell lines was due to promoter region hypermethylation, and overexpressing Clca2 in negative cell lines reduced their tumorigenicity and metastasis capability [7]. Depletion of Clca2 led to accelerated senescence onset in UVB and Nutlin3a-induced senescence models, and in 3D skin equivalent models, Clca2 knockdown fibroblasts exhibited aged-like skin features [3]. In keratinocytes, Clca2 is transported to the nucleus via extracellular vesicles, where it binds to and activates β-catenin, affecting cell survival and migration [4]. In human mammary epithelial cells, knockdown of Clca2 caused EMT, and it was found to interact with EVA1, which is essential for epithelial differentiation [5].

In conclusion, Clca2 is a key regulator in multiple biological processes. Through various gene-based functional studies including loss-of-function experiments, its role in cancer development, cellular senescence, and skin homeostasis has been revealed. These findings suggest Clca2 as a potential therapeutic target for cancers like cervical and breast cancer, and further understanding of its functions could provide new insights into disease mechanisms and treatment strategies.