Deciphering the Functional Role of RIPK4 in Melanoma
The receptor-interacting protein kinase 4 (RIPK4) plays an important role in the development and maintenance of various tissues including skin, but its role in melanoma has not been reported. Using patient-derived cell lines and clinical samples, we show that RIPK4 is expressed in melanomas at diffe...
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2021
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oai:doaj.org-article:fe5554cd6a21484a979e22f93da62d282021-11-11T16:57:58ZDeciphering the Functional Role of RIPK4 in Melanoma10.3390/ijms2221115041422-00671661-6596https://doaj.org/article/fe5554cd6a21484a979e22f93da62d282021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11504https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The receptor-interacting protein kinase 4 (RIPK4) plays an important role in the development and maintenance of various tissues including skin, but its role in melanoma has not been reported. Using patient-derived cell lines and clinical samples, we show that RIPK4 is expressed in melanomas at different levels. This heterogenous expression, together with very low level of RIPK4 in melanocytes, indicates that the role of this kinase in melanoma is context-dependent. While the analysis of microarray data has revealed no straightforward correlation between the stage of melanoma progression and RIPK4 expression in vivo, relatively high levels of RIPK4 are in metastatic melanoma cell lines. RIPK4 down-regulation by siRNA resulted in the attenuation of invasive potential as assessed by time-lapse video microscopy, wound-healing and transmigration assays. These effects were accompanied by reduced level of pro-invasive proteins such as MMP9, MMP2, and N-cadherin. Incubation of melanoma cells with phorbol ester (PMA) increased PKC-1β level and hyperphosphorylation of RIPK4 resulting in degradation of RIPK4. Interestingly, incubation of cells with PMA for short and long durations revealed that cell migration is controlled by the NF-κB signaling in a RIPK4-dependent (RIPK4<sup>high</sup>) or independent (RIPK4<sup>low</sup>) manner depending on cell origin (distant or lymph node metastasis) or phenotype (mesenchymal or epithelial).Ewelina MadejDamian RyszawyAnna A. BrożynaMalgorzata CzyzJaroslaw CzyzAgnieszka Wolnicka-GlubiszMDPI AGarticleinvasive potentialmelanomaMMPsNF-κBRIPK4Biology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11504, p 11504 (2021) |
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| collection |
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| language |
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| topic |
invasive potential melanoma MMPs NF-κB RIPK4 Biology (General) QH301-705.5 Chemistry QD1-999 |
| spellingShingle |
invasive potential melanoma MMPs NF-κB RIPK4 Biology (General) QH301-705.5 Chemistry QD1-999 Ewelina Madej Damian Ryszawy Anna A. Brożyna Malgorzata Czyz Jaroslaw Czyz Agnieszka Wolnicka-Glubisz Deciphering the Functional Role of RIPK4 in Melanoma |
| description |
The receptor-interacting protein kinase 4 (RIPK4) plays an important role in the development and maintenance of various tissues including skin, but its role in melanoma has not been reported. Using patient-derived cell lines and clinical samples, we show that RIPK4 is expressed in melanomas at different levels. This heterogenous expression, together with very low level of RIPK4 in melanocytes, indicates that the role of this kinase in melanoma is context-dependent. While the analysis of microarray data has revealed no straightforward correlation between the stage of melanoma progression and RIPK4 expression in vivo, relatively high levels of RIPK4 are in metastatic melanoma cell lines. RIPK4 down-regulation by siRNA resulted in the attenuation of invasive potential as assessed by time-lapse video microscopy, wound-healing and transmigration assays. These effects were accompanied by reduced level of pro-invasive proteins such as MMP9, MMP2, and N-cadherin. Incubation of melanoma cells with phorbol ester (PMA) increased PKC-1β level and hyperphosphorylation of RIPK4 resulting in degradation of RIPK4. Interestingly, incubation of cells with PMA for short and long durations revealed that cell migration is controlled by the NF-κB signaling in a RIPK4-dependent (RIPK4<sup>high</sup>) or independent (RIPK4<sup>low</sup>) manner depending on cell origin (distant or lymph node metastasis) or phenotype (mesenchymal or epithelial). |
| format |
article |
| author |
Ewelina Madej Damian Ryszawy Anna A. Brożyna Malgorzata Czyz Jaroslaw Czyz Agnieszka Wolnicka-Glubisz |
| author_facet |
Ewelina Madej Damian Ryszawy Anna A. Brożyna Malgorzata Czyz Jaroslaw Czyz Agnieszka Wolnicka-Glubisz |
| author_sort |
Ewelina Madej |
| title |
Deciphering the Functional Role of RIPK4 in Melanoma |
| title_short |
Deciphering the Functional Role of RIPK4 in Melanoma |
| title_full |
Deciphering the Functional Role of RIPK4 in Melanoma |
| title_fullStr |
Deciphering the Functional Role of RIPK4 in Melanoma |
| title_full_unstemmed |
Deciphering the Functional Role of RIPK4 in Melanoma |
| title_sort |
deciphering the functional role of ripk4 in melanoma |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/fe5554cd6a21484a979e22f93da62d28 |
| work_keys_str_mv |
AT ewelinamadej decipheringthefunctionalroleofripk4inmelanoma AT damianryszawy decipheringthefunctionalroleofripk4inmelanoma AT annaabrozyna decipheringthefunctionalroleofripk4inmelanoma AT malgorzataczyz decipheringthefunctionalroleofripk4inmelanoma AT jaroslawczyz decipheringthefunctionalroleofripk4inmelanoma AT agnieszkawolnickaglubisz decipheringthefunctionalroleofripk4inmelanoma |
| _version_ |
1718432217841008640 |