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Tumor Biology

, Volume 36, Issue 1, pp 315–327 | Cite as

Hu-antigen receptor (HuR) and cyclooxygenase-2 (COX-2) expression in human non-small-cell lung carcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients’ survival

  • Constantinos Giaginis
  • Paraskevi Alexandrou
  • Nikolaos Tsoukalas
  • Ioannis Sfiniadakis
  • Nikolaos Kavantzas
  • Emmanuel Agapitos
  • Efstratios Patsouris
  • Stamatios Theocharis
Research Article

Abstract

Hu-antigen R (HuR) is considered to play a central role in tumor formation, growth, and metastasis by binding to messenger RNAs (mRNAs) encoding proteins such as cyclooxygenase-2 (COX-2) and inducing their expression via mRNA stabilization and/or altered translation. The present study aimed to evaluate the clinical significance of HuR and COX-2 protein expression in non-small-cell lung carcinoma (NSCLC). HuR and COX-2 expression was assessed immunohistochemically on tissue microarrays of 81 surgically resected NSCLC and was analyzed in relation with clinicopathological characteristics and patients’ survival. Enhanced total HuR expression was significantly associated with tumor histological type and presence of lymph node metastases, as well as with increased tumor proliferative capacity and poor patients’ outcome (p = 0.039, p = 0.017, p = 0.033, and p = 0.022, respectively). Enhanced COX-2 expression was significantly associated with the presence of lymphovascular invasion and increased tumor proliferative capacity (p = 0.031 and p = 0.023, respectively). Concomitant elevated HuR/COX-2 expression levels were significantly associated with tumor histological type and increased proliferative capacity (p = 0.002 and p = 0.045, respectively). Enhanced total HuR expression, as well as its cytoplasmic localization, was significantly associated with increased COX-2 expression (p = 0.015 and p = 0.001, respectively). The present study supported evidence that HuR may participate in malignant transformation of NSCLC, reinforcing its usefulness as potential therapeutic target in this type of neoplasia.

Keywords

HuR COX-2 Non-small-cell lung carcinoma Clinicopathological parameters Prognosis Immunohistochemistry 

Notes

Acknowledgments

We would like to thank Mr George Vilaras for his excellent technical assistance.

Conflicts of interest

All authors verify that they have not accepted any funding or support from an organization that may in any way gain or lose financially from the results of the present study. All authors verify that they have not been employed by an organization that may in any way gain or lose financially from the results of the present study. None authors have any other conflicting interest.

References

  1. 1.
    Ma WJ, Cheng S, Campbell C, Wright A, Furneaux H. Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J Biol Chem. 1996;271:8144–51.CrossRefPubMedGoogle Scholar
  2. 2.
    Ma WJ, Furneaux H. Localization of the human HuR gene to chromosome 19p13.2. Hum Genet. 1997;99:32–3.CrossRefPubMedGoogle Scholar
  3. 3.
    Burd CG, Dreyfuss G. Conserved structures and diversity of functions of RNA-binding proteins. Science. 1994;265:615–21.CrossRefPubMedGoogle Scholar
  4. 4.
    Lopez de Silanes I, Lopezde Silanes I, Zhan M, Lal A, Yang X, Zhan M, et al. Identification of a target RNA motif for RNA-binding protein HuR. Proc Natl Acad Sci USA. 2004;101:2987–92.CrossRefPubMedGoogle Scholar
  5. 5.
    Fan XC, Steitz JA. HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc Natl Acad Sci U S A. 1998;95:15293–8.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Abdelmohsen K, Lal A, Kim HH, Gorospe M. Posttranscriptional orchestration of an anti-apoptotic program by HuR. Cell Cycle. 2007;6:1288–92.CrossRefPubMedGoogle Scholar
  7. 7.
    Yiakouvaki A, Dimitriou M, Karakasiliotis I, Eftychi C, Theocharis S, Kontoyiannis DL. Myeloid cell expression of the RNA-binding protein HuR protects mice from pathologic inflammation and colorectal carcinogenesis. J Clin Invest. 2012;122:48–61.CrossRefPubMedGoogle Scholar
  8. 8.
    Khan Z, Khan N, Tiwari RP, Sah NK, Prasad GB, Bisen PS. Biology of Cox-2: an application in cancer therapeutics. Curr Drug Targets. 2011;12:1082–93.CrossRefPubMedGoogle Scholar
  9. 9.
    Ghosh N, Chaki R, Mandal V, Mandal SC. COX-2 as a target for cancer chemotherapy. Pharmacol Rep. 2010;62:233–44.CrossRefPubMedGoogle Scholar
  10. 10.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.CrossRefPubMedGoogle Scholar
  11. 11.
    D’ Addario G, Felip E. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20:68–70.CrossRefGoogle Scholar
  12. 12.
    Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer: looking to the future. J Clin Oncol. 2005;23:3175–85.CrossRefPubMedGoogle Scholar
  13. 13.
    Méndez D, Alshanqeety O, Warner KE, Lantz PM, Courant PN. The impact of declining smoking on radon-related lung cancer in the United States. Am J Public Health. 2011;101:310–4.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Rhee WJ, Ni CW, Zheng Z, Chang K, Jo H, Bao G. HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells. Proc Natl Acad Sci U S A. 2010;107:6858–63.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Zhang J, Modi Y, Yarovinsky T, et al. Macrophage beta2 integrin-mediated, HuR-dependent stabilization of angiogenic factor-encoding mRNAs in inflammatory angiogenesis. Am J Pathol. 2012;180:1751–60.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lopez de Silanes I, Fan J, Yang X, et al. Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene. 2003;22:7146–54.CrossRefPubMedGoogle Scholar
  17. 17.
    Lopez de Silanes I, Lal A, Gorospe M. HuR: post-transcriptional paths to malignancy. RNA Biol. 2005;2:11–3.CrossRefPubMedGoogle Scholar
  18. 18.
    Abdelmohsen K, Srikantan S, Kuwano Y, Gorospe M. miR-519 reduces cell proliferation by lowering RNA-binding protein HuR levels. Proc Natl Acad Sci USA. 2008;105:20297–302.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Abdelmohsen K, Kim MM, Srikantan S, Abdelmohsen K, Kim MM, Srikantan S, et al. miR-519 suppresses tumor growth by reducing HuR levels. Cell Cycle. 2010;9:1354–9.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Abdelmohsen K, Gorospe M. Posttranscriptional regulation of cancer traits by HuR. Wiley Interdiscip Rev RNA. 2010;1:214–29.CrossRefPubMedGoogle Scholar
  21. 21.
    Srikantan S, Gorospe M. HuR function in disease. Front Biosci (Landmark Ed). 2012;17:189–205.CrossRefGoogle Scholar
  22. 22.
    Yuan Z, Sanders AJ, Ye L, Jiang WG. HuR, a key post-transcriptional regulator, and its implication in progression of breast cancer. Histol Histopathol. 2010;25:1331–40.PubMedGoogle Scholar
  23. 23.
    Kotta-Loizou I, Giaginis C, Theocharis S. Clinical significance of HuR expression in human malignancy. Med Oncol. 2014;31:161.CrossRefPubMedGoogle Scholar
  24. 24.
    Greene FLPD, Fleming ID, Fritz AG, Balch CM, Haller DG, Morrow M. AJCC cancer staging manual. 6th ed. New York: Springer; 2002.CrossRefGoogle Scholar
  25. 25.
    Nair A, Klusmann MJ, Jogeesvaran KH, Grubnic S, Green SJ, Vlahos I. Revisions to the TNM Staging of Non-Small Cell Lung Cancer: Rationale, Clinicoradiologic Implications, and Persistent Limitations. Radiographics. 2011;31:215–38.CrossRefPubMedGoogle Scholar
  26. 26.
    Lababede O, Meziane M, Rice T. Seventh edition of the cancer staging manual and stage grouping of lung cancer: quick reference chart and diagrams. Chest. 2011;139:183–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Theocharis S, Klijanienko J, Giaginis C, Alexandrou P, Patsouris E, Sastre-Garau X. FAK and Src expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival. J Cancer Res Clin Oncol. 2012;138:1369–77.CrossRefPubMedGoogle Scholar
  28. 28.
    Giaginis C, Alexandrou P, Delladetsima I, Giannopoulou I, Patsouris E, Theocharis S. Clinical significance of histone deacetylase (HDAC)-1, HDAC-2, HDAC-4, and HDAC-6 expression in human malignant and benign thyroid lesions. Tumour Biol. 2014;35:61–71.CrossRefPubMedGoogle Scholar
  29. 29.
    Giaginis C, Politi E, Alexandrou P, Sfiniadakis J, Kouraklis G, Theocharis S. Expression of peroxisome proliferator activated receptor-gamma (PPAR-γ) in human non-small cell lung carcinoma: correlation with clinicopathological parameters, proliferation and apoptosis related molecules and patients’ survival. Pathol Oncol Res. 2012;18875–83.:Google Scholar
  30. 30.
    Theocharis S, Klijanienko J, Giaginis C, et al. Peroxisome proliferator-activated receptor-γ in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival. J Cancer Res Clin Oncol. 2011;137:251–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Young LE, Moore AE, Sokol L, Meisner-Kober N, Dixon DA. The mRNA stability factor HuR inhibits microRNA-16 targeting of COX-2. Mol Cancer Res. 2012;10:167–80.CrossRefPubMedGoogle Scholar
  32. 32.
    Huang RY, Li SS, Guo HZ, et al. Thromboxane A2 exerts promoting effects on cell proliferation through mediating cyclooxygenase-2 signal in lung adenocarcinoma cells. J Cancer Res Clin Oncol. 2014;140:375–86.CrossRefPubMedGoogle Scholar
  33. 33.
    Wang J, Wang B, Bi J, Zhang C. Cytoplasmic HuR expression correlates with angiogenesis, lymphangiogenesis, and poor outcome in lung cancer. Med Oncol. 2011;28:S577–85.CrossRefPubMedGoogle Scholar
  34. 34.
    Kim GY, Lim SJ, Kim YW. Expression of HuR, COX-2, and survivin in lung cancers; cytoplasmic HuR stabilizes cyclooxygenase-2 in squamous cell carcinomas. Mod Pathol. 2011;24:1336–47.CrossRefPubMedGoogle Scholar
  35. 35.
    Lauriola L, Granone P, Ramella S, Lanza P, Ranelletti FO. Expression of the RNA-binding protein HuR and its clinical significance in human stage I and II lung adenocarcinoma. Histol Histopathol. 2012;27:617–26.PubMedGoogle Scholar
  36. 36.
    Stoppoloni D, Cardillo I, Verdina A, et al. Expression of the embryonic lethal abnormal vision-like protein HuR in human mesothelioma: association with cyclooxygenase-2 and prognosis. Cancer. 2008;113:2761–9.CrossRefPubMedGoogle Scholar
  37. 37.
    Filippova N, Yang X, Wang Y, et al. The RNA-binding protein HuR promotes glioma growth and treatment resistance. Mol Cancer Res. 2011;9:648–59.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Hostetter C, Licata LA, Witkiewicz A, et al. Cytoplasmic accumulation of the RNA binding protein HuR is central to tamoxifen resistance in estrogen receptor positive breast cancer cells. Cancer Biol Ther. 2008;7:1496–506.CrossRefPubMedGoogle Scholar
  39. 39.
    Costantino CL, Witkiewicz AK, Kuwano Y, et al. The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res. 2009;69:4567–72.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Williams TK, Costantino CL, Bildzukewicz NA, et al. pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs. PLoS One. 2010;5:e15455.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    McAllister F, Pineda DM, Jimbo M, et al. dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer: A dual-institutional follow-up with the RTOG 9704 trial. Cancer Biol Ther. 2014;15:688–98.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Constantinos Giaginis
    • 1
    • 2
  • Paraskevi Alexandrou
    • 1
  • Nikolaos Tsoukalas
    • 3
  • Ioannis Sfiniadakis
    • 4
  • Nikolaos Kavantzas
    • 1
  • Emmanuel Agapitos
    • 1
  • Efstratios Patsouris
    • 1
  • Stamatios Theocharis
    • 1
  1. 1.First Department of Pathology, Medical SchoolNational and Kapodistrian University of AthensAthensGreece
  2. 2.Department of Food Science and Nutrition, School of the EnvironmentUniversity of the Aegean, MyrinaLemnosGreece
  3. 3.Department of Medical Oncology401 General Military HospitalAthensGreece
  4. 4.Department of PathologyNaval HospitalAthensGreece

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