Skip to main content

Advertisement

SpringerLink
Log in

Tissue Microarray Analysis of 560 Patients with Colorectal Adenocarcinoma: High Expression of HuR Predicts Poor Survival

  • Laboratory and Translational Research
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

The purpose of this study is to characterize the expression of HuR in colorectal carcinoma and determine its correlation with clinical outcome. Differential expression of HuR has been suggested to be of prognostic significance in carcinomas of the ovaries, stomach, and breast. HuR regulates the expression of a variety of proteins critical to carcinogenesis via the pathways of cell-cycle progress, invasion, and metastasis. Increasing evidence suggests that angiogenic pathways are involved. A tissue microarray consisting of tumors from 560 patients with colorectal adenocarcinoma was analyzed for HuR protein expression using a quantitative, automated immunofluorescent microscopy system (AQUA). Clinical data corresponding to each examined specimen collected through an institutional review board (IRB)-approved protocol were analyzed using chi-squared test, Cox regression, and Kaplan–Meier analysis. Median follow-up was 54 months. Along with tumor stage and overall tumor–node–metastasis (TNM) stage, HuR expression was found to be an independent predictor of survival. In patients in the highest quartile of total HuR expression, survival was 22.8 months less than those in the lower quartiles (40.6 versus 63.4 months, p = 0.04). Furthermore, HuR levels correlate positively with expression of vascular endothelial growth factor (VEGF) and CD31, a marker for vascular endothelium. We conclude that expression of high levels of HuR correlates with features of advanced disease and portends poorer survival in patients with colorectal adenocarcinoma. These results further suggest that HuR exerts its tumorigenic effects through VEGF-mediated angiogenesis and may be a novel therapeutic target in colorectal cancer.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57(1):43–66.

    Article  PubMed  Google Scholar 

  2. Yoo PS, Lopez-Soler RI, Longo WE, Cha CH. Liver resection for metastatic colorectal cancer in the age of neoadjuvant chemotherapy and bevacizumab. Clin Colorectal Cancer. 2006;6(3):202–7.

    Article  CAS  PubMed  Google Scholar 

  3. Maindrault-Goebel F, de Gramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Oncology Multidisciplinary Research Group (GERCOR). Ann Oncol. 2000;11(11):1477–83.

    Article  CAS  PubMed  Google Scholar 

  4. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.

    Article  CAS  PubMed  Google Scholar 

  5. Viloria-Petit A, Crombet T, Jothy S, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res. 2001;61(13):5090–101.

    CAS  PubMed  Google Scholar 

  6. Yoo PS, Mulkeen AL, Cha CH. Post-transcriptional regulation of vascular endothelial growth factor: implications for tumor angiogenesis. World J Gastroenterol. 2006;12(31):4937–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fan XHC, Steitz JA. Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs. EMBO J. 1998;17(12):3448–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Peng SS, Chen CY, Xu N, Shyu AB. RNA stabilization by the AU-rich element binding protein, HuR, an ELAV protein. EMBO J. 1998;17(12):3461–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. de Silanes IL, Fan JS, Yang XL, et al. Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene. 2003;22(46):7146–54.

    Article  Google Scholar 

  10. Lopez de Silanes I, Lal A, Gorospe M. HuR: post-transcriptional paths to malignancy. RNA Biol. 2005;2(1):11–3.

    Article  CAS  PubMed  Google Scholar 

  11. Blaxall BC, Dwyer-Nield LD, Bauer AK, Bohlmeyer TJ, Malkinson AM, Port JD. Differential expression and localization of the mRNA binding proteins, AU-rich element mRNA binding protein (AUF1) and Hu antigen R (HuR), in neoplastic lung tissue. Mol Carcinog. 2000;28(2):76–83.

    Article  CAS  PubMed  Google Scholar 

  12. Denkert C, Weichert W, Pest S, et al. Overexpression of the embryonic-lethal abnormal vision-like protein HuR in ovarian carcinoma is a prognostic factor and is associated with increased cyclooxygenase 2 expression. Cancer Res. 2004;64(1):189–95.

    Article  CAS  PubMed  Google Scholar 

  13. Denkert C, Weichert W, Winzer KJ, et al. Expression of the ELAV-like protein HuR is associated with higher tumor grade and increased cyclooxygenase-2 expression in human breast carcinoma. Clin Cancer Res. 2004;10(16):5580–6.

    Article  CAS  PubMed  Google Scholar 

  14. Levy AP, Levy NS, Goldberg MA. Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J Biol Chem. 1996;271(5):2746–53.

    Article  CAS  PubMed  Google Scholar 

  15. Stein I, Neeman M, Shweiki D, Itin A, Keshet E. Stabilization of vascular endothelial growth factor mRNA by hypoxia and hypoglycemia and coregulation with other ischemia-induced genes. Mol Cell Biol. 1995;15(10):5363–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Galban S, Kuwano Y, Pullmann R Jr, et al. RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1alpha. Mol Cell Biol. 2008;28(1):93–107.

    Article  CAS  PubMed  Google Scholar 

  17. Lejbkowicz F, Goldberg-Cohen I, Levy AP. New horizons for VEGF. Is there a role for nuclear localization? Acta Histochem. 2005;106(6):405–11.

    Article  CAS  PubMed  Google Scholar 

  18. Denkert C, Koch I, von Keyserlingk N, et al. Expression of the ELAV-like protein HuR in human colon cancer: association with tumor stage and cyclooxygenase-2. Mod Pathol. 2006;19(9):1261–9.

    Article  CAS  PubMed  Google Scholar 

  19. Camp RL, Chung GG, Rimm DL. Automated subcellular localization and quantification of protein expression in tissue microarrays. Nat Med. 2002;8(11):1323–7.

    Article  CAS  PubMed  Google Scholar 

  20. Rimm DL, Camp RL, Charette LA, Costa J, Olsen DA, Reiss M. Tissue microarray: a new technology for amplification of tissue resources. Cancer J. 2001;7(1):24–31.

    CAS  PubMed  Google Scholar 

  21. Katoh AK, Stemmler N, Specht S, D’Amico F. Immunoperoxidase staining for estrogen and progesterone receptors in archival formalin fixed, paraffin embedded breast carcinomas after microwave antigen retrieval. Biotech Histochem. 1997;72(6):291–8.

    Article  CAS  PubMed  Google Scholar 

  22. Lopez de Silanes I, Quesada MP, Esteller M. Aberrant regulation of messenger RNA 3′-untranslated region in human cancer. Cell Oncol. 2007;29(1):1–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Heinonen M, Fagerholm R, Aaltonen K, et al. Prognostic role of HuR in hereditary breast cancer. Clin Cancer Res. 2007;13(23):6959–63.

    Article  CAS  PubMed  Google Scholar 

  24. Brennan CM, Steitz JA. HuR and mRNA stability. Cell Mol Life Sci. 2001;58(2):266–77.

    Article  CAS  PubMed  Google Scholar 

  25. Bossi P, Viale G, Lee AK, Alfano R, Coggi G, Bosari S. Angiogenesis in colorectal tumors: microvessel quantitation in adenomas and carcinomas with clinicopathological correlations. Cancer Res. 1995;55(21):5049–53.

    CAS  PubMed  Google Scholar 

  26. Gulubova M, Vlaykova T. Prognostic significance of mast cell number and microvascular density for the survival of patients with primary colorectal cancer. J Gastroenterol Hepatol. 2007 [Epub ahead of print].

  27. Abdelmohsen K, Lal A, Kim HH, Gorospe M. Posttranscriptional orchestration of an anti-apoptotic program by HuR. Cell Cycle. 2007;6(11):1288–92.

    Article  CAS  PubMed  Google Scholar 

  28. Guo X, Hartley RS. HuR contributes to cyclin E1 deregulation in MCF-7 breast cancer cells. Cancer Res. 2006;66(16):7948–56.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, Yale University School of Medicine, New Haven, USA

    Peter S. Yoo MD, Sharon Kiang MD, Wenli Gao PhD, Edward M. Uchio MD & Charles H. Cha MD

  2. Department of Medicine, Yale University School of Medicine, New Haven, USA

    Catherine A. W. Sullivan MS & Gina G. Chung MD

Authors
  1. Peter S. Yoo MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catherine A. W. Sullivan MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sharon Kiang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenli Gao PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Edward M. Uchio MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gina G. Chung MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Charles H. Cha MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charles H. Cha MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoo, P.S., Sullivan, C.A.W., Kiang, S. et al. Tissue Microarray Analysis of 560 Patients with Colorectal Adenocarcinoma: High Expression of HuR Predicts Poor Survival. Ann Surg Oncol 16, 200–207 (2009). https://doi.org/10.1245/s10434-008-0209-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-008-0209-3

Keywords

Search

Navigation