The Prognostic Relevance of PMCA4 Expression in Melanoma: Gender Specificity and Implications for Immune Checkpoint Inhibition

Luca Hegedüs, Elisabeth Livingstone, Ágnes Bánkfalvi, Jan Viehof, Ágnes Enyedi, Ágnes Bilecz, Balázs Győrffy, Marcell Baranyi, Anna Mária Tőkés, Jeovanis Gil, György Marko-Varga, Klaus G. Griewank, Lisa Zimmer, Renáta Váraljai, Antje Sucker, Anne Zaremba, Dirk Schadendorf, Clemens Aigner, Balázs Hegedüs

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning

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.

Originalspråkengelska
Artikelnummer3324
TidskriftInternational Journal of Molecular Sciences
Volym23
Nummer6
DOI
StatusPublished - 2022 mars 1

Ämnesklassifikation (UKÄ)

  • Cell- och molekylärbiologi

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