Foxo3a suppression of urothelial cancer invasiveness through Twist1, Y-box-binding protein 1, and E-cadherin regulation.
OBJECTIVE
Invasion and metastasis are key steps in the progression of urothelial cancer (UC) into a critical disease. Foxo3a is a member of the Foxo transcription factor family that modulates the expression of various genes. We aimed to elucidate the role of Foxo3a in UC invasion.


METHODS
Foxo3a mRNA and protein expressions in UC samples were investigated by gene expression assays and immunohistochemistry, respectively. Foxo3a expression was compared with clinicopathologic characteristics and patient prognoses based on UC samples. Quantitative real-time polymerase chain reaction, Western blotting, and migration assays were also conducted in UC cells.


RESULTS
Foxo3a expression decreased in invasive UC; patients with low Foxo3a expression had poor disease-free survival, cancer-specific survival, and overall survival; Foxo3a knockdown in UC cells increased cellular motility. Foxo3a negatively regulated Twist1 and Y-box-binding protein 1 (YB-1), and positively regulated E-cadherin in KK47 and TCCsup cells that expressed Twist1, but not in T24 cells that did not express Twist1. Foxo3a-associated acetyltransferase p300 and Foxo3a acetylation status also affected UC motility.


CONCLUSIONS
The results of this study indicate that Foxo3a regulates motility of UC through negative regulation of Twist1 and YB-1, and through positive regulation of E-cadherin. This suggests that Foxo3a could act as an independent prognostic factor in UC and could represent a promising molecular target for cancer therapeutics.
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Masaki
M
Shiota
YooHyun
Y
Song
Akira
A
Yokomizo
Keijiro
K
Kiyoshima
Yasuhiro
Y
Tada
Hiroshi
H
Uchino
Takeshi
T
Uchiumi
Junichi
J
Inokuchi
Yoshinao
Y
Oda
Kentaro
K
Kuroiwa
Katsunori
K
Tatsugami
Seiji
S
Naito
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D002277:Carcinoma / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D019459:Urothelium / Q000473:pathology; D051840:Y-Box-Binding Protein 1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
D014408:Biomarkers, Tumor; D015820:Cadherins; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D051840:Y-Box-Binding Protein 1