p16(INK4A) inhibits the pro-metastatic potentials of osteosarcoma cells through targeting the ERK pathway and TGF-β1

Molecular Carcinogenesis
Gabriela Silva, Abdelilah Aboussekhra

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. p16(INK4A) 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 p16(INK4A) 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 p16(INK4) inhibits the migration/invasion abilities of these cells through miR-21-5p-dependent inhibition of ERK1/2. In addition, we present clear evidence that p16(INK4) represses the paracrine pro-migratory effect of osteosarcoma cel...Continue Reading

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Citations

Jun 14, 2016·Biochemistry. Biokhimii︠a︡·N E KushlinskiiE A Braga
Oct 12, 2019·Journal of Cellular Physiology·Luigi SapioSilvio Naviglio
Dec 13, 2017·Oncotarget·Manjula NakkaUNKNOWN TARGET osteosarcoma consortium
Mar 15, 2019·FEBS Open Bio·Siqi DongLixin Dong
Oct 18, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Seung Wan SonJong Kook Park
Oct 27, 2020·Cell Proliferation·Zheng LiWilliam K K Wu

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