Clca2, short for Calcium-activated chloride channel A2, is a transmembrane protein with diverse functions. It has been implicated in multiple biological processes, often functioning as a tumor suppressor. It is associated with pathways like Wnt/β -catenin, ERK/JNK/p38-MAPK, and is involved in regulating calcium-activated chloride channel currents and store-operated calcium entry [1,2,5]. Genetic models, such as gene knockout models, can be valuable for further exploring its functions.

In cervical cancer, Clca2 expression is decreased compared to adjacent normal tissues. Its up-regulation is associated with longer survival times, and knockdown of Clca2 by small interfering RNA suppresses tumor cell proliferation and migration, suggesting it suppresses the proliferation, migration, and invasion of cervical cancer cells [1].

In breast cancer, CLCA2 is frequently inactivated by promoter region hypermethylation, and when overexpressed in CLCA2-negative cell lines, their tumorigenicity and metastasis capability are significantly reduced [7]. In African American women with triple negative breast cancer, CLCA2 expression is associated with overall survival [6].

Additionally, 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]. Depletion of Clca2 in UVB and Nutlin3a-induced senescence models led to accelerated senescence onset, highlighting its role in cellular senescence and potentially skin aging [3].

In conclusion, Clca2 is a crucial protein with significant implications in multiple disease areas, especially cancer. Its functions in suppressing tumor cell behaviors in cervical and breast cancer, as well as its role in cellular senescence, have been revealed through various studies. Gene knockout models could potentially further clarify its functions in these and other biological processes and disease conditions.