The Prognostic Relevance of PMCA4 Expression in Melanoma : Gender Specificity and Implications for Immune Checkpoint Inhibition
(2022) In International Journal of Molecular Sciences 23(6).- Abstract
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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2022-03-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Immune checkpoint inhibition, Lung metastasis, Melanoma, Plasma membrane calcium ATPase 4
- in
- International Journal of Molecular Sciences
- volume
- 23
- issue
- 6
- article number
- 3324
- publisher
- MDPI AG
- external identifiers
-
- scopus:85126688156
- pmid:35328746
- ISSN
- 1661-6596
- DOI
- 10.3390/ijms23063324
- language
- English
- LU publication?
- yes
- id
- 695e7f0b-f11e-4c74-a312-511f73b0e63d
- date added to LUP
- 2022-06-09 11:00:52
- date last changed
- 2024-06-13 15:45:36
@article{695e7f0b-f11e-4c74-a312-511f73b0e63d,
abstract = {{<p>PMCA4 is a critical regulator of Ca<sup>2+</sup> 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.</p>}},
author = {{Hegedüs, Luca and Livingstone, Elisabeth and Bánkfalvi, Ágnes and Viehof, Jan and Enyedi, Ágnes and Bilecz, Ágnes and Győrffy, Balázs and Baranyi, Marcell and Tőkés, Anna Mária and Gil, Jeovanis and Marko-Varga, György and Griewank, Klaus G. and Zimmer, Lisa and Váraljai, Renáta and Sucker, Antje and Zaremba, Anne and Schadendorf, Dirk and Aigner, Clemens and Hegedüs, Balázs}},
issn = {{1661-6596}},
keywords = {{Immune checkpoint inhibition; Lung metastasis; Melanoma; Plasma membrane calcium ATPase 4}},
language = {{eng}},
month = {{03}},
number = {{6}},
publisher = {{MDPI AG}},
series = {{International Journal of Molecular Sciences}},
title = {{The Prognostic Relevance of PMCA4 Expression in Melanoma : Gender Specificity and Implications for Immune Checkpoint Inhibition}},
url = {{http://dx.doi.org/10.3390/ijms23063324}},
doi = {{10.3390/ijms23063324}},
volume = {{23}},
year = {{2022}},
}