The tumor-suppressor gene Nkx2.8 suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway.
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 G(1)/S phase arrest, accompanied by upregulation of p27(Kip1), downregulation of cyclin D1 and p-FOXO3a and inhibition of MEK/ERK pathway activity. Meanwhile, silencing Nkx2.8 led to acceleration of G(1)/S transition, downregulation of p27(Kip1), 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.
State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Chunping
C
Yu
Zhiling
Z
Zhang
Wenting
W
Liao
Xiaohui
X
Zhao
Liping
L
Liu
Yanheng
Y
Wu
Zhuowei
Z
Liu
Yonghong
Y
Li
Yi
Y
Zhong
Kun
K
Chen
Jun
J
Li
Fangjian
F
Zhou
Libing
L
Song
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis; D018450:Disease Progression; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011379:Prognosis; D059807:S Phase Cell Cycle Checkpoints / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D001743:Urinary Bladder / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D014408:Biomarkers, Tumor; C436291:CDKN1B protein, human; D018797:Cell Cycle Proteins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; C108070:NKX2-8 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020928:Mitogen-Activated Protein Kinases