PMCA4 is a critical regulator of Ca2+ homeostasis in mammalian cells. While its biological
and prognostic relevance in several cancer types has already been demonstrated, only
preclinical investigations suggested a metastasis suppressor function in melanoma.
Therefore, we studied the expression pattern of PMCA4 in human skin, nevus, as well
as in primary and metastatic melanoma using immunohistochemistry. Furthermore, we
analyzed the prognostic power of PMCA4 mRNA levels in cutaneous melanoma both at the
non-metastatic stage as well as after PD-1 blockade in advanced disease. PMCA4 localizes
to the plasma membrane in a differentiation dependent manner in human skin and mucosa,
while nevus cells showed no plasma membrane staining. In contrast, primary cutaneous,
choroidal and conjunctival melanoma cells showed specific plasma membrane localization
of PMCA4 with a wide range of intensities. Analyzing the TCGA cohort, PMCA4 mRNA levels
showed a gender specific prognostic impact in stage I-III melanoma. Female patients
with high transcript levels had a significantly longer progression-free survival.
Melanoma cell specific PMCA4 protein expression is associated with anaplasticity in
melanoma lung metastasis but had no impact on survival after lung metastasectomy.
Importantly, high PMCA4 transcript levels derived from RNA-seq of cutaneous melanoma
are associated with significantly longer overall survival after PD-1 blockade. In
summary, we demonstrated that human melanoma cells express PMCA4 and PMCA4 transcript
levels carry prognostic information in a gender specific manner.
