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

• Published in: International journal of molecular sciences Vol. 23; no. 6; p. 3324
• Main Authors: Hegedüs, Luca, Livingstone, Elisabeth, Bánkfalvi, Ágnes, Viehof, Jan, Enyedi, Ágnes, Bilecz, Ágnes, Győrffy, Balázs, Baranyi, Marcell, Tőkés, Anna-Mária, Gil, Jeovanis, Marko-Varga, György, Griewank, Klaus G, Zimmer, Lisa, Váraljai, Renáta, Sucker, Antje, Zaremba, Anne, Schadendorf, Dirk, Aigner, Clemens, Hegedüs, Balázs
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 19-03-2022; MDPI
• Subjects: Animals; Basic Medicine; Binding sites; Biomarkers; Calcium homeostasis; Calcium ions; Cancer therapies; Cell adhesion & migration; Cell and Molecular Biology; Cell- och molekylärbiologi; Colorectal cancer; Female; Gender; Gene expression; Homeostasis; Humans; Immune checkpoint; Immune checkpoint inhibition; Immune Checkpoint Inhibitors; Immunohistochemistry; Localization; Lung cancer; Lung metastasis; Lungs; Mammalian cells; Mammals - metabolism; Medical and Health Sciences; Medical prognosis; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Melanoma; Melanoma - genetics; Melanoma, Cutaneous Malignant; Membranes; Metastases; Metastasis; Mucosa; Mutation; Nevus; PD-1 protein; Plasma membrane calcium ATPase 4; Plasma Membrane Calcium-Transporting ATPases - metabolism; Prognosis; Programmed Cell Death 1 Receptor - metabolism; Proteins; RNA, Messenger; Skin cancer; Skin Neoplasms - genetics; Survival; Transcription; Vagina; melanoma; lung metastasis; immune checkpoint inhibition; plasma membrane calcium ATPase 4
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23063324

PMCA4 is a critical regulator of Ca
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.