Markers of squamous cell carcinoma in sarco/endoplasmic reticulum Ca 2+ ATPase 2 heterozygote mice keratinocytes

Abstract

A mutation of Atp2a2 gene encoding the sarco/endoplasmic reticulum Ca 2+-ATPase 2 (SERCA2) causes Darier's disease in human and null mutation in one copy of Atp2a2 leads to a high incidence of squamous cell tumor in a mouse model. In SERCA2 heterozygote (SERCA2 +/−) mice keratinocytes, mechanisms involved in partial depletion of SERCA2 gene and its related tumor induction have not been studied. In this study, we investigated Ca 2+ signaling and differential gene expression in primary cultured keratinocytes from SERCA2 +/− mice. SERCA2 +/− keratinocytes showed reduced initial increases in intracellular concentration of calcium in response to ATP, a G-protein coupled receptor agonist, and higher store-operated Ca 2+ entry with the treatment of thapsigargin, an inhibitor of SERCA, compared to wild type kerationcytes. Protein expressions of plasma membrane Ca 2+ ATPases, NFATc1, phosphorylated ERK, JNK, and phospholipase γ1 were increased in SERCA2 +/− keratinocytes. Using the gene fishing system, we first found in SERCA2 +/− keratinocytes that gene level of tumor-associated calcium signal transducer 1, crystalline αB, procollagen XVIII α1, and nuclear factor I-B were increased. Expression of involucrin, a marker of keratinocyte differentiation, was decreased in SERCA2 +/− keratinocytes. These results suggest that the alterations of Ca 2+ signaling by SERCA2 haploinsufficiency alternate the gene expression of tumor induction and differentiation in keratinocytes.