Korean J Urol.  2007 Apr;48(4):396-401. 10.4111/kju.2007.48.4.396.

The Expression and Clinical Implications of Forkhead Trasnscription Factor FKHR (FOXO1) in Human Bladder Cancer

Affiliations
  • 1Department of Urology, College of Medicine, Konkuk University, Chungju, Korea.
  • 2Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea. wjkim@chungbuk.ac.kr

Abstract

PURPOSE
Forkhead transcription factor FKHR (FOXO1) is one member of the Forkhead transcription factor family, and it is thought to regulate the glucose metabolism in human and to be related to both cell cycle progression and cell apoptosis. Herein, we investigated the expression level of FOXO1 and its clinical implications in bladder cancer.
MATERIALS AND METHODS
From June 1992 to June 2005, 145 specimens were harvested from primary bladder cancer and 102 specimens were harvested from normal-looking tissue surrounding the tumor mass; these specimens were investigated for determining the mRNA expression levels of FOXO1 with using the real-time PCR method. The expression levels of FOXO1 were compared statistically with such clinical variables as stage, grade, recurrence and progression. Survival analysis was performed using the Kaplan-Meier model.
RESULTS
The expression levels of FOXO1 in the bladder cancer specimens (28.19pg/ml) were significantly higher than those of the corresponding normal bladder tissues (8.87pg/ml) that surrounded the tumor mass (p<0.001), and the expression levels of FOXO1 were significantly correlated with stage and the progression of superficial disease (p<0.05 each). Also, the expressions of FOXO1 of the patients who remained alive during the study period were higher than those of the nonsurviving patients (p<0.001). A higher expression of FOXO1 in the patients with superficial bladder tumor showed more survival benefit than a lower expression (p=0.004). But the recurrence and differentiation of bladder cancer were not correlated with the expression level of FOXO1.
CONCLUSIONS
This data indicate that the expression level of FOXO1 can be recommended as a useful marker to predict disease occurrence as well as the progression and survival of patients with superficial bladder cancer.

Keyword

FKHR protein; Bladder cancer; Polymerase chain reaction

MeSH Terms

Apoptosis
Cell Cycle
Glucose
Humans*
Metabolism
Polymerase Chain Reaction
Real-Time Polymerase Chain Reaction
Recurrence
RNA, Messenger
Transcription Factors
Urinary Bladder Neoplasms*
Urinary Bladder*
Glucose
RNA, Messenger
Transcription Factors

Figure

  • Fig. 1 Kaplan-Meier survival curve according to the expression level of FOXO1 in human bladder cancer. Both the high and low FOXO1 groups are divided by the median value (9.91pg/ml) of FOXO1.


Reference

1. Kim WJ, Yoon SJ. Current trend in molecular aspects of bladder cancer. Korean J Urol. 2005. 46:211–220.
2. Jacobson MD, Weil M, Raff MC. Programmed cell death in animal development. Cell. 1997. 88:347–354.
3. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science. 1998. 281:1305–1308.
4. Evan G, Littlewood T. A matter of life and cell death. Science. 1998. 281:1317–1322.
5. Huang H, Tindall DJ. FOXO factors: a matter of life and death. Future Oncol. 2006. 2:83–89.
6. May P, May E. Twenty years of p53 research: structural and functional aspects of the p53 protein. Oncogene. 1999. 18:7621–7636.
7. Katoh M, Katoh M. Human FOX gene family (review). Int J Oncol. 2004. 25:1495–1500.
8. Furukawa-Hibi Y, Kobayashi Y, Chen C, Motoyama N. FOXO transcription factors in cell-cycle regulation and the response to oxidative stress. Antioxid Redox Signal. 2005. 7:752–760.
9. Burgering BM, Kops GJ. Cell cycle and death control: long live Forkheads. Trends Biochem Sci. 2002. 27:352–360.
10. Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A. Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci USA. 2003. 100:11285–11290.
11. Li P, Lee H, Guo S, Unterman TG, Jenster G, Bai W. AKT-independent protection of prostate cancer cells from apoptosis mediated through complex formation between the androgen receptor and FKHR. Mol Cell Biol. 2003. 23:104–118.
12. Modur V, Nagarajan R, Evers BM, Milbrandt J. FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J Biol Chem. 2002. 277:47928–47937.
13. Nakamura N, Ramaswamy S, Vazquez F, Signoretti S, Loda M, Sellers WR. Forkhead transcription factors are critical effectors of cell death and cell cycle arrest downstream of PTEN. Mol Cell Biol. 2000. 20:8969–8982.
14. Medema RH, Kops GJ, Bos JL, Burgering BM. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature. 2000. 404:782–787.
15. Alvarez B, Martinez-A C, Burgering BM, Carrera AC. Forkhead transcription factors contribute to execution of the mitotic programme in mammals. Nature. 2001. 413:744–747.
16. Bennicelli JL, Edwards RH, Barr FG. Mechanism for transcriptional gain of function resulting from chromosomal translocation in alveolar rhabdomyosarcoma. Proc Natl Acad Sci USA. 1996. 93:5455–5459.
17. Li J, Thurm H, Chang HW, Iacovoni JS, Vogt PK. Oncogenic transformation induced by the Qin protein is correlated with transcriptional repression. Proc Natl Acad Sci USA. 1997. 94:10885–10888.
18. Li J, Vogt PK. The retroviral oncogene qin belongs to the transcription factor family that includes the homeotic gene fork head. Proc Natl Acad Sci USA. 1993. 90:4490–4494.
19. Tao W, Lai E. Telencephalon-restricted expression of BF-1, a new member of the HNF-3/fork head gene family, in the developing rat brain. Neuron. 1992. 8:957–966.
20. Aoki M, Jiang H, Vogt PK. Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. Proc Natl Acad Sci USA. 2004. 101:13613–13617.
21. Yang Y, Hou H, Haller EM, Nicosia SV, Bai W. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J. 2005. 24:1021–1032.
Full Text Links
  • KJU
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr