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1.
Sci Rep ; 14(1): 1525, 2024 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-38233537

RESUMEN

The combination of oncogenes and tumor suppressors is involved in cancer development; however, it is still unknown whether their combination plays a critical role in cancer metastasis. We herein investigated whether genetic combinations affected cell migration ability by establishing the immortalized melanocytes, melan-a cells, with an oncogene, either BRAFV600E or GNA11Q209L, and the loss of mouse Pten. The loss of mouse Pten or human PTEN increased the cell migration ability of our established cells and human melanoma cell lines with oncogenic MAPK signaling and the BRAFV600E or NRASQ61R background, but not with the GNA11Q209L background or no oncogenes. Although increased migration was not related to PI3K-AKT activation, those migration is regulated by the induction of some components in the WAVE regulatory complex, resulting in a higher rate of the formation of lamellipodia. On the other hand, BRAFV600E induced EphA2 phosphorylation at serine 897 through RSK and was also required for cell migration and the formation of lamellipodia. Therefore, the oncogenic MAPK pathway and loss of Pten in melanoma were important for cell migration through the formation of lamellipodia, suggesting the significance of an appropriate combination of genetic alterations not only in cancer development, but also cancer metastasis.


Asunto(s)
Melanoma , Animales , Humanos , Ratones , Línea Celular Tumoral , Melanocitos/metabolismo , Melanoma/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Seudópodos/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo
2.
Sci Rep ; 10(1): 19214, 2020 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-33154524

RESUMEN

Although melanoma therapy is improved by novel molecular targeted reagents, including vemurafenib, aberrant proliferation and early metastasis remain obstacles for melanoma; therefore, novel target molecules for melanoma need to be identified. In this study, we focused on deubiquitinating enzymes, which regulate protein stability through ubiquitin-proteasome systems, and identified 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) as a molecule related to melanoma growth using siRNA library screening. Similar to a previous report, PSMD14 knockdown strongly induced p21 expression and inhibited RB phosphorylation in melanoma. After in silico analysis, TGF-ß signaling was identified as a negatively correlated gene set with PSMD14 expression. Although TGF-ß signaling is also related to the invasive phenotype of melanoma, PSMD14 knockdown suppressed melanoma migration and reduced SLUG expression, suggesting that targeting PSMD14 suppresses both growth and migration. Furthermore, SMAD3 expression increased in nucleus and SMAD3 degradation was delayed after PSMD14 knockdown. Thus, our present study suggests that targeting PSMD14 can inhibit melanoma growth and migration through either SMAD3 accumulation or SLUG reduction, respectively.


Asunto(s)
Proliferación Celular/fisiología , Melanoma/genética , Complejo de la Endopetidasa Proteasomal/genética , Neoplasias Cutáneas/genética , Proteína smad3/genética , Transactivadores/genética , Línea Celular Tumoral , Técnicas de Silenciamiento del Gen , Humanos , Melanoma/metabolismo , Melanoma/patología , Fosforilación , Complejo de la Endopetidasa Proteasomal/metabolismo , ARN Interferente Pequeño , Transducción de Señal/fisiología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Proteína smad3/metabolismo , Transactivadores/metabolismo , Factor de Crecimiento Transformador beta/metabolismo
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