Journal Article

The tumor-suppressor gene <i>Nkx2.8</i> suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway

Chunping Yu, Zhiling Zhang, Wenting Liao, Xiaohui Zhao, Liping Liu, Yanheng Wu, Zhuowei Liu, Yonghong Li, Yi Zhong, Kun Chen, Jun Li, Fangjian Zhou and Libing Song

in Carcinogenesis

Volume 33, issue 3, pages 678-686
Published in print March 2012 | ISSN: 0143-3334
Published online January 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgr321
The tumor-suppressor gene Nkx2.8 suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway

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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 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 upregulation of p27Kip1, downregulation of cyclin D1 and p-FOXO3a and inhibition of MEK/ERK pathway activity. Meanwhile, silencing Nkx2.8 led to acceleration of G1/S transition, downregulation of p27Kip1, upregulation 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.

Journal Article.  5416 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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