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- W2163530629 abstract "Extracellular signal-regulated kinase (ERK) is a downstream component of the evolutionarily conserved mitogen-activated protein kinase-signaling pathway, which controls the expression of a plethora of genes implicated in various physiological processes. This pathway is often hyper-activated by mutations or abnormal extracellular signaling in different types of human cancer, including the most common primary malignant bone tumor osteosarcomas. p16INK4A is an important tumor suppressor gene frequently lost in osteosarcomas, and is associated with the progression of these malignancies. We have shown, here, that the ERK1/2 protein kinase is also activated by p16INK4A down-regulation in osteosarcoma cells and normal human as well as mouse cells. This inhibitory effect is associated with the suppression of the upstream kinase MEK1/2, and is mediated via the repression of miR-21-5p and the consequent up-regulation of the MEK/ERK antagonist SPRY2 in osteosarcoma cells. Furthermore, we have shown that p16INK4 inhibits the migration/invasion abilities of these cells through miR-21-5p-dependent inhibition of ERK1/2. In addition, we present clear evidence that p16INK4 represses the paracrine pro-migratory effect of osteosarcoma cells on stromal fibroblasts through the inhibition of the TGF-β1 expression/secretion. This effect is also ERK1/2-dependent, indicating that in addition to their cell-autonomous actions, p16INK4 and ERK1/2 have also non-cell-autonomous cancer-related functions. Together, these results indicate that the tumor suppressor p16INK4 protein represses the carcinogenic process of osteosarcoma cells not only as a cell cycle regulator, but also as a negative regulator of pro-carcinogenic/-metastatic pathways. This indicates that targeting the ERK pathway is of utmost therapeutic value. © 2015 Wiley Periodicals, Inc." @default.
- W2163530629 created "2016-06-24" @default.
- W2163530629 creator A5028947927 @default.
- W2163530629 creator A5038471270 @default.
- W2163530629 date "2015-03-01" @default.
- W2163530629 modified "2023-09-30" @default.
- W2163530629 title "p16<sup>INK4A</sup> inhibits the pro-metastatic potentials of osteosarcoma cells through targeting the ERK pathway and TGF-β1" @default.
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- W2163530629 doi "https://doi.org/10.1002/mc.22299" @default.
- W2163530629 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25728247" @default.
- W2163530629 hasPublicationYear "2015" @default.
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