Top

Published in:

01-12-2009 | Original Paper

The Expression and Prognosis of FOXO3a and Skp2 in Human Hepatocellular Carcinoma

Authors: Mudan Lu, Jianbo Ma, Wenqun Xue, Chun Cheng, You Wang, Yueming Zhao, Qing Ke, Haiou Liu, Yonghua Liu, Peng Li, Xiaopeng Cui, Song He, Aiguo Shen

Published in: Pathology & Oncology Research | Issue 4/2009

Abstract

The forkhead box proteins (FOXO proteins) comprise a large family of functionally diverse transcription factors involved in cellular proliferation, transformation, differentiation and longevity. Recently, ubiquitination and proteasome degradation of FOXO3a have been reported. In this study, we investigated the role of FOXO3a and Skp2 in human hepatocellular carcinoma progression. Immunohistochemical analysis was performed on formalin-fixed paraffin sections of 91 specimens. Furthermore in vitro, western-blot analysis and protein stabilization studies were used to study the relationship between FOXO3a and Skp2. We found that the expression of FOXO3a was negatively related with Skp2 expression (r = −0.583; p < 0.05) and FOXO3a expression correlated significantly with histological grade (p = 0.000), cirrhosis (p = 0.015), and tumor size (p = 0.043) while Skp2 expression correlated significantly with histological grade (p = 0.000) and tumor size (p = 0.005). Kaplan-Meier analysis revealed that survival curves of low versus high expressers of FOXO3a and Skp2 showed a highly significant separation in HCC (p < 0.01). Our results suggested that FOXO3a and Skp2 may be considered to be important prognosis in human hepatocellular carcinoma. In vitro studies suggested that the degradation of FOXO3a may dependent on the expression of Skp2 in the proliferated Huh7 cells.

Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC (1998) Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. Genomics 47:187–199CrossRefPubMed

Aoki M, Jiang H, Vogt PK (2004) Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. Proc Natl Acad Sci U S A 101:13613–13617CrossRefPubMed

Borkhardt A, Repp R, Haas OA, Leis T, Harbott J, Kreuder J, Hammermann J et al (1997) Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23). Oncogene 14:195–202CrossRefPubMed

Bosch FX, Ribes J, Borràs J (1999) Epidemiology of primary liver cancer. Semin Liver Dis 19:271–285CrossRefPubMed

Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868CrossRefPubMed

Chakravarthy MV, Abraha TW, Schwartz RJ, Fiorotto ML, Booth FW (2000) Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3'-kinase/Akt signaling pathway. J Biol Chem 275:35942–35952CrossRefPubMed

el-Serag HB (2001) vi. Epidemiology of hepatocellular carcinoma. Clin Liver Dis 5:87–107CrossRefPubMed

Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ 3rd, Emanuel BS, Rovera G et al (1993) Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 5:230–235CrossRefPubMed

Gilley J, Coffer PJ, Ham J (2003) FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 162:613–622CrossRefPubMed

10.

Greer EL, Brunet A (2005) FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24:7410–7425CrossRefPubMed

11.

Hromas R, Costa R (1995) The hepatocyte nuclear factor-3/forkhead transcription regulatory family in development, inflammation, and neoplasia. Crit Rev Oncol Hematol 20:129–140CrossRefPubMed

12.

Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, Zou Y et al (2004) IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117:225–237CrossRefPubMed

13.

Huang H, Regan KM, Wang F, Wang D, Smith DI, van Deursen JM, Tindall DJ (2005) Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci U S A 102:1649–1654CrossRefPubMed

14.

Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP (2003) FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 278:35959–35967CrossRefPubMed

15.

Kaufmann E, Knöchel W (1996) Five years on the wings of fork head. Mech Dev 57:3–20CrossRefPubMed

16.

Lai E, Clark KL, Burley SK, Darnell JE Jr (1993) Hepatocyte nuclear factor 3/fork head or "winged helix" proteins: a family of transcription factors of diverse biologic function. Proc Natl Acad Sci U S A 90:10421–104233CrossRefPubMed

17.

Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A (2003) Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci U S A 100:11285–11290CrossRefPubMed

18.

Medema RH, Kops GJ, Bos JL, Burgering BM (2000) AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27^kip1. Nature 404:782–787CrossRefPubMed

19.

Modur V, Nagarajan R, Evers BM, Milbrandt J (2002) FOXO proteins regulate tumor necrosis factor-related apoptosis inducing ligand expression. Implications for PTEN mutation in prostate cancer. J Biol Chem. 277:47928–47937CrossRefPubMed

20.

Parkin DM, Bray F, Ferlay J, Pisani P (2001) Estimating the world cancer burden: Globocan 2000. Int J Cancer 94:153–156CrossRefPubMed

21.

Plas DR, Thompson CB (2003) Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J Biol Chem 278:12361–12366CrossRefPubMed

22.

Potente M, Urbich C, Sasaki K, Hofmann WK, Heeschen C, Aicher A, Kollipara R et al (2005) Involvement of Foxo transcription factors in angiogenesis and postnatal neovascularization. J Clin Invest 115:2382–2392CrossRefPubMed

23.

Ramaswamy S, Nakamura N, Sansal I, Bergeron L, Sellers WR (2002) A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell 2:81–91CrossRefPubMed

24.

Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129–1136CrossRefPubMed

25.

Xu X, Yamamoto H, Sakon M, Yasui M, Ngan CY, Fukunaga H, Morita T et al (2003) Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas. Clin Cancer Res 9:1764–1772PubMed

Title: The Expression and Prognosis of FOXO3a and Skp2 in Human Hepatocellular Carcinoma
Authors: Mudan Lu
Jianbo Ma
Wenqun Xue
Chun Cheng
You Wang
Yueming Zhao
Qing Ke
Haiou Liu
Yonghua Liu
Peng Li
Xiaopeng Cui
Song He
Aiguo Shen
Publication date: 01-12-2009
Publisher: Springer Netherlands
Published in: Pathology & Oncology Research / Issue 4/2009
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-009-9171-z

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2009

Molecular Changes in Primary Breast Tumors and the Nottingham Histologic Score

The Effect of LMWH (Nadroparin) on Tumor Progression

Immunohistochemical Prognostic Markers in Intracranial Ependymomas: Systematic Review and Meta-Analysis

Reduced APRIL Expression Induces Cellular Senescence via a HSPG-Dependent Pathway

Prognostic Value of Tumor-Related Molecular Expression in Gastric Carcinoma

Hairy Cell Leukemia-Related Disorders Consistently Show Low CD27 Expression

Keynote webinar | Spotlight on antibody–drug conjugates in cancer