Skip to main content

Advertisement

Log in

Overexpression of AGGF1 is correlated with angiogenesis and poor prognosis of hepatocellular carcinoma

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Angiogenic factor with G-patch and FHA domains 1 (AGGF1) is a factor implicating in vascular differentiation and angiogenesis. Several lines of evidence indicate that aberrant expression of AGGF1 is associated with tumor initiation and progression. The aim of this study was to investigate the expression and prognostic value of AGGF1 in hepatocellular carcinoma (HCC), as well as its relationship with clinicopathological factors and tumor angiogenesis. Immunohistochemistry was performed to evaluate the expression of AGGF1 in HCC and paracarcinomatous tissues collected from 70 patients. Vascular endothelial growth factor (VEGF) and CD34 expression levels were examined in the 70 HCC tissues. Prognostic significance of tumoral AGGF1 expression was determined. Notably, AGGF1 expression was significantly higher in HCC than in surrounding non-tumor tissues (65.7 vs. 25.7 %; P < 0.001). AGGF1 expression was significantly correlated with tumoral VEGF expression and CD34-positive microvessel density. Moreover, AGGF1 expression was significantly associated with tumor size, tumor capsule, vascular invasion, Edmondson grade, alpha-fetoprotein level, and TNM stage. Kaplan–Meier survival analysis showed that high AGGF1 was correlated with reduced overall survival (OS) rate (P = 0.001) and disease-free survival (DFS) rate (P < 0.001). Multivariate analysis identified AGGF1 as an independent poor prognostic factor of OS and DFS in HCC patients (P = 0.043 and P = 0.010, respectively). Taken together, increased AGGF1 expression is associated with tumor angiogenesis and serves as an independent unfavorable prognostic factor for OS and DFS in HCC. AGGF1 may represent a potential therapeutic target for HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

AFP:

Alpha-fetoprotein

AGGF1:

Angiogenic factor with G-patch and forkhead-associated domain 1

DAB:

3,3-diaminobenzidine tetrahydrochloride

DFS:

Disease-free survival

HBsAg:

Hepatitis B s antigen

HCC:

Hepatocellular carcinoma

HE:

Hematoxylin and eosin

KTS:

Klippel–Trenaunay syndrome

MVD:

Microvessel density

OS:

Overall survival

PBS:

Phosphate-buffered saline

TNM:

Tumor-node-metastasis

UICC:

International Union Against Cancer

VEGF:

Vascular endothelial growth factor

References

  1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.

    Article  CAS  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  3. Blechacz B, Mishra L. Hepatocellular carcinoma biology. Recent Results Cancer Res. 2013;190:1–20.

    Article  PubMed  Google Scholar 

  4. Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol. 2004;41:864–80.

    Article  PubMed  Google Scholar 

  5. Bishayee A, Darvesh AS. Angiogenesis in hepatocellular carcinoma: a potential target for chemoprevention and therapy. Curr Cancer Drug Targets. 2012;12:1095–118.

    CAS  PubMed  Google Scholar 

  6. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353–64.

    Article  CAS  PubMed  Google Scholar 

  7. Muto J, Shirabe K, Sugimachi K, Maehara Y. Review of angiogenesis in hepatocellular carcinoma. Hepatol Res. 2015;45:1–9.

    Article  PubMed  Google Scholar 

  8. Finsterbusch T, Steinfeldt T, Doberstein K, Rodner C, Mankertz A. Interaction of the replication proteins and the capsid protein of porcine circovirus type 1 and 2 with host proteins. Virology. 2009;386:122–31.

    Article  CAS  PubMed  Google Scholar 

  9. Tian XL, Kadaba R, You SA, Liu M, Timur AA, Yang L, et al. Identification of an angiogenic factor that when mutated causes susceptibility to Klippel–Trenaunay syndrome. Nature. 2004;427:640–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Hu Y, Li L, Seidelmann SB, Timur AA, Shen PH, Driscoll DJ, et al. Identification of association of common AGGF1 variants with susceptibility for Klippel–Trenaunay syndrome using the structure association program. Ann Hum Genet. 2008;72:636–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Chen D, Li L, Tu X, Yin Z, Wang Q. Functional characterization of Klippel–Trenaunay syndrome gene AGGF1 identifies a novel angiogenic signaling pathway for specification of vein differentiation and angiogenesis during embryogenesis. Hum Mol Genet. 2013;22:963–76.

    Article  CAS  PubMed  Google Scholar 

  12. Lu Q, Yao Y, Yao Y, Liu S, Huang Y, Lu S, et al. Angiogenic factor AGGF1 promotes therapeutic angiogenesis in a mouse limb ischemia model. PLoS One. 2012;7:e46998.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies. Cancer. 1954;7:462–503.

    Article  CAS  PubMed  Google Scholar 

  14. Sun QK, Zhu JY, Wang W, Lv Y, Zhou HC, Yu JH, et al. Diagnostic and prognostic significance of peroxiredoxin 1 expression in human hepatocellular carcinoma. Med Oncol. 2014;31:786.

    Article  PubMed  Google Scholar 

  15. Kudo Y, Ogawa I, Kitajima S, Kitagawa M, Kawai H, Gaffney PM, et al. Periostin promotes invasion and anchorage-independent growth in the metastatic process of head and neck cancer. Cancer Res. 2006;66:6928–35.

    Article  CAS  PubMed  Google Scholar 

  16. Fan C, Ouyang P, Timur AA, He P, You SA, Hu Y, et al. Novel roles of GATA1 in regulation of angiogenic factor AGGF1 and endothelial cell function. J Biol Chem. 2009;284:23331–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Liu Y, Yang H, Song L, Li N, Han QY, Tian C, et al. AGGF1 protects from myocardial ischemia/reperfusion injury by regulating myocardial apoptosis and angiogenesis. Apoptosis. 2014;19:1254–68.

    Article  CAS  PubMed  Google Scholar 

  18. Xu Y, Zhou M, Wang J, Zhao Y, Li S, Zhou B, et al. Role of microRNA-27a in down-regulation of angiogenic factor AGGF1 under hypoxia associated with high-grade bladder urothelial carcinoma. Biochim Biophys Acta. 2014;1842:712–25.

    Article  CAS  PubMed  Google Scholar 

  19. Roe OD, Anderssen E, Sandeck H, Christensen T, Larsson E, Lundgren S. Malignant pleural mesothelioma: genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets. Lung Cancer. 2010;67:57–68.

    Article  PubMed  Google Scholar 

  20. Tanigawa N, Lu C, Mitsui T, Miura S. Quantitation of sinusoid-like vessels in hepatocellular carcinoma: its clinical and prognostic significance. Hepatology. 1997;26:1216–23.

    CAS  PubMed  Google Scholar 

  21. Kaya M, Wada T, Akatsuka T, Kawaguchi S, Nagoya S, Shindoh M, et al. Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clin Cancer Res. 2000;6:572–7.

    CAS  PubMed  Google Scholar 

  22. Yoshiji H, Kuriyama S, Noguchi R, Yoshii J, Ikenaka Y, Yanase K, et al. Angiopoietin 2 displays a vascular endothelial growth factor dependent synergistic effect in hepatocellular carcinoma development in mice. Gut. 2005;54:1768–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Major MB, Roberts BS, Berndt JD, Marine S, Anastas J, Chung N, et al. New regulators of Wnt/beta-catenin signaling revealed by integrative molecular screening. Sci Signal. 2008;1:ra12.

    PubMed  Google Scholar 

  24. Easwaran V, Lee SH, Inge L, Guo L, Goldbeck C, Garrett E, et al. beta-Catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res. 2003;63:3145–53.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was partly supported by the National Natural Science Foundation of China (No. 81201906).

Conflict of interest

The authors declare that they have no competing financial interests.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chu-Shu Ji.

Additional information

Wei Wang, Guang-Yao Li, and Jian-Yu Zhu have contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 71 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, W., Li, GY., Zhu, JY. et al. Overexpression of AGGF1 is correlated with angiogenesis and poor prognosis of hepatocellular carcinoma. Med Oncol 32, 131 (2015). https://doi.org/10.1007/s12032-015-0574-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-015-0574-2

Keywords

Navigation