The tumor-suppressor gene Nkx2.8 suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway
Menée sur des lignées cellulaires et des échantillons de tissus sains et tumoraux prélevés sur des patients atteints d'un cancer invasif de la vessie, cette étude suggère que le gène Nkx2.8 exerce une fonction de suppresseur de tumeurs
Invasive bladder cancer is a lethal disease for which effective prognostic markers as well as potential therapy targets are still lacking. Nkx2.8 (Nk2 homeobox 8), a novel member of the the NK-2 gene family, was reported to play an important role in the development and progression of human cancer. Herein, we reported that Nkx2.8 was markedly reduced in bladder cancer tissues compared with matched adjacent normal urothelial tissues. Nkx2.8 levels were inversely correlated with advanced T classification, N classification, tumor multiplicity, high proliferation index (Ki-67) and poor survival of patients. Furthermore, we found that overexpression of Nkx2.8 in bladder cancer cells significantly inhibited cell proliferation in vitro and in vivo, whereas silencing Nkx2.8 dramatically enhanced cell proliferation. Moreover, we demonstrated that overexpression of Nkx2.8 resulted in G1/S phase arrest, accompanied by up-regulation of p27Kip1, down-regulation of cyclin D1 and p-FOXO3a, and inhibition of MEK/ERK pathway activity. Meanwhile, silencing Nkx2.8 led to acceleration of G1/S transition, down-regulation of p27Kip1, up-regulation of cyclin D1 and p-FOXO3a, and increase of MEK/ERK pathway activity. These findings suggest that Nkx2.8 plays a potential tumor suppressor role in bladder cancer progression and represents a valuable clinical prognostic marker of this disease.
http://carcin.oxfordjournals.org/content/early/2012/01/04/carcin.bgr321.abstract