Skip to main content
Erschienen in: Medical Oncology 2/2012

01.06.2012 | Original Paper

The expression and significance of pThr32-FOXO3a in human ovarian cancer

verfasst von: Mudan Lu, Jingying Xiang, Fei Xu, Yong Wang, Yongxiang Yin, Daozhen Chen

Erschienen in: Medical Oncology | Ausgabe 2/2012

Einloggen, um Zugang zu erhalten

Abstract

FOXO3a possesses a large series function, including cellular proliferation, transformation, differentiation, and longevity. Recent studies suggested that the different localization of FOXO3a in nucleus and cytoplasm has different functions. And phosphorylation of FOXO3a at threonine-32 plays an important role in deciding FOXO3a localization. In this study, we investigated the role of pThr32-FOXO3a and Ki-67 in human ovarian cancer. Furthermore, we study the effect of mutant of FOXO3a (T32A) on the ovarian cancer cells. Immunohistochemical analysis was performed on formalin-fixed paraffin sections of 46 specimens. And in vitro, we detect the contribution of wild-type and mutant FOXO3a on the ovarian cancer cell proliferation. We found that the pThr32-FOXO3a was overexpressed in human ovarian cancer, and pThr32-FOXO3a expression correlated significantly with lymph node involvement (P = 0.015). And the proliferation index Ki-67 was significantly associated with lymph node involvement (P = 0.000) and disease stage (P = 0.003). Kaplan–Meier analysis revealed that survival curves of low versus high expressers of pThr32-FOXO3a and Ki-67 showed a highly significant separation in human ovarian cancer (P < 0.01). Transfection of FOXO3a (T32A) resulted in a significant increase in cells in G1 phase than transfection of wild-type FOXO3a and control cells. Our results suggested that pThr32-FOXO3a and Ki-67 expression may be considered to be important prognosis in human ovarian cancer. In vitro studies suggested that FOXO3a (T32A) was a more powerful cell cycle inhibitor, although both the wild type and mutant forms of FOXO3a were effective.
Literatur
1.
Zurück zum Zitat Ries LAG, Kosary CL, Hankey BF., Miller BA, Clegg L, and Edwards BK SEER Cancer statistics review. national cancer institute. Ries LAG, Kosary CL, Hankey BF., Miller BA, Clegg L, and Edwards BK SEER Cancer statistics review. national cancer institute.
2.
Zurück zum Zitat Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2004;117:421–6.PubMedCrossRef Accili D, Arden KC. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell. 2004;117:421–6.PubMedCrossRef
3.
Zurück zum Zitat Hu MC, Lee DF, Xia W, et al. InB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004;117:225–37.PubMedCrossRef Hu MC, Lee DF, Xia W, et al. InB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004;117:225–37.PubMedCrossRef
4.
Zurück zum Zitat Yang JY, Zong CS. XiaW, et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10:138–48.PubMedCrossRef Yang JY, Zong CS. XiaW, et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10:138–48.PubMedCrossRef
5.
Zurück zum Zitat Paik JH, Kollipara R, Chu G, et al. FoxOs arelineagerestricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell. 2007;128:309–23.PubMedCrossRef Paik JH, Kollipara R, Chu G, et al. FoxOs arelineagerestricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell. 2007;128:309–23.PubMedCrossRef
6.
Zurück zum Zitat Fei M, Zhao Y, Wang Y, et al. A low expression of FOXO3a is associated with poor prognosis in ovarian cancer patients. Cancer Invest. 2009;27(1):52–9.PubMedCrossRef Fei M, Zhao Y, Wang Y, et al. A low expression of FOXO3a is associated with poor prognosis in ovarian cancer patients. Cancer Invest. 2009;27(1):52–9.PubMedCrossRef
7.
Zurück zum Zitat Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96:857–68.PubMedCrossRef Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96:857–68.PubMedCrossRef
8.
Zurück zum Zitat Cattoretti G, Becker MH, Key G, Duchrow M, Galle J, et al. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992;168:357–63.PubMedCrossRef Cattoretti G, Becker MH, Key G, Duchrow M, Galle J, et al. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992;168:357–63.PubMedCrossRef
9.
Zurück zum Zitat Benjamin DR. Proliferating cell nuclear antigen (PCNA) and pediatric tumors: assessment of proliferative activity. Pediatr Pathol. 1991;11:507–19.PubMedCrossRef Benjamin DR. Proliferating cell nuclear antigen (PCNA) and pediatric tumors: assessment of proliferative activity. Pediatr Pathol. 1991;11:507–19.PubMedCrossRef
10.
Zurück zum Zitat Khine MM, Aung W, Sibbons PD, Howard CV, Clapham E, et al. Analysis of relative proliferation rates of Wilms’ tumor components using proliferating cell nuclear antigen and MIB-1 (Ki-67 equivalent antigen) immunostaining and assessment of mitotic index. Lab Invest. 1994;70:125–9.PubMed Khine MM, Aung W, Sibbons PD, Howard CV, Clapham E, et al. Analysis of relative proliferation rates of Wilms’ tumor components using proliferating cell nuclear antigen and MIB-1 (Ki-67 equivalent antigen) immunostaining and assessment of mitotic index. Lab Invest. 1994;70:125–9.PubMed
11.
Zurück zum Zitat Delahunt B, Farrant GJ, Bethwaite PB, Nacey JN, Lewis ME. Assessment of proliferative activity in Wilms’ tumour. Anal Cell Pathol. 1994;7:127–38.PubMed Delahunt B, Farrant GJ, Bethwaite PB, Nacey JN, Lewis ME. Assessment of proliferative activity in Wilms’ tumour. Anal Cell Pathol. 1994;7:127–38.PubMed
12.
Zurück zum Zitat Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24:7410–25.PubMedCrossRef Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24:7410–25.PubMedCrossRef
13.
Zurück zum Zitat Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by ph osphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96:857–68.PubMedCrossRef Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by ph osphorylating and inhibiting a Forkhead transcription factor. Cell. 1999;96:857–68.PubMedCrossRef
14.
Zurück zum Zitat Yang JY, Zong CS, Xia W. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10:138–48.PubMedCrossRef Yang JY, Zong CS, Xia W. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10:138–48.PubMedCrossRef
15.
Zurück zum Zitat Myatt SS. Lam EW.The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 2007;7:847–59.PubMedCrossRef Myatt SS. Lam EW.The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 2007;7:847–59.PubMedCrossRef
16.
Zurück zum Zitat Dong XY, Chen C, Sun X, et al. FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. Cancer Res. 2006;66:6998–7006.PubMedCrossRef Dong XY, Chen C, Sun X, et al. FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. Cancer Res. 2006;66:6998–7006.PubMedCrossRef
Metadaten
Titel
The expression and significance of pThr32-FOXO3a in human ovarian cancer
verfasst von
Mudan Lu
Jingying Xiang
Fei Xu
Yong Wang
Yongxiang Yin
Daozhen Chen
Publikationsdatum
01.06.2012
Verlag
Springer US
Erschienen in
Medical Oncology / Ausgabe 2/2012
Print ISSN: 1357-0560
Elektronische ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-011-9919-7

Weitere Artikel der Ausgabe 2/2012

Medical Oncology 2/2012 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.