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PLEKHA5 regulates tumor growth in metastatic melanoma
- Source :
- Cancer
- Publication Year :
- 2019
- Publisher :
- Wiley, 2019.
-
Abstract
- Background PLEKHA5 has previously been identified as a novel molecule implicated in melanoma brain metastasis, a disease that continues to portend a poor prognosis. The aim of this study was to further investigate the functional role of PLEKHA5 in disseminated melanoma. Methods The impact of PLEKHA5 on proliferation and tumor growth was examined in vitro and in melanoma xenograft models, including brain-tropic melanomas (melanomas tending to disseminate to the brain). In vitro loss- and gain-of-function studies were used to explore the underlying mechanisms of PLEKHA5-mediated tumor growth and the crosstalk between PLEKHA5 and PI3K/AKT/mTOR or MAPK/ERK signaling. The clinical relevance of PLEKHA5 dysregulation was further investigated in a cohort of matched cranial and extracranial melanoma metastases. Results PLEKHA5 stable knockdown negatively regulated cell proliferation by inhibiting the G1 -to-S cell cycle transition, which coincided with upregulation of the cell cycle regulator PDCD4. Conversely, ectopic PLEKHA5 expression exhibited the inverse effect. PLEKHA5 knockdown significantly inhibited tumor growth, whereas its overexpression upregulated the growth of tumors, which was induced by cranial and subcutaneous inoculation of cells in nude mice. PLEKHA5 modulation affected PDCD4 protein stability and was coupled with changes in PI3K/AKT/mTOR pathway signaling. High PDCD4 expression in cerebral specimens was associated with better overall survival. Conclusions This study further supports the role of PLEKHA5 as a regulator of melanoma growth at distant sites, including the brain. Furthermore, the results highlight the significance of PDCD4 dysregulation in disseminated melanoma and implicate PDCD4 as a possible causal link between PLEKHA5 and cell proliferation and growth.
- Subjects :
- Adult
Male
MAPK/ERK pathway
Cancer Research
Mice, Nude
Article
Mice
Phosphatidylinositol 3-Kinases
Young Adult
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Biomarkers, Tumor
Tumor Cells, Cultured
medicine
Animals
Humans
030212 general & internal medicine
Melanoma
Protein kinase B
PI3K/AKT/mTOR pathway
Aged
Cell Proliferation
Gene knockdown
Brain Neoplasms
Cell growth
business.industry
TOR Serine-Threonine Kinases
Intracellular Signaling Peptides and Proteins
Middle Aged
Cell cycle
Prognosis
medicine.disease
Xenograft Model Antitumor Assays
Gene Expression Regulation, Neoplastic
Oncology
030220 oncology & carcinogenesis
Cancer research
Female
Apoptosis Regulatory Proteins
business
Proto-Oncogene Proteins c-akt
Follow-Up Studies
Subjects
Details
- ISSN :
- 10970142 and 0008543X
- Volume :
- 126
- Database :
- OpenAIRE
- Journal :
- Cancer
- Accession number :
- edsair.doi.dedup.....3202ce186dd7f2255e8906b4a29bda67