HuR is a member of the family of ELAV (embryonic lethal abnormal vision)-like proteins that stabilize several cellular mRNAs by binding to AU-rich elements in the 3’ untranslated region of the mRNA. Cyclooxygenase-2 (COX-2) is a well known enzyme that promotes tumor growth and metastasis. Recent studies have shown that HuR can stabilize the mRNA of COX-2, and cytoplasmic expression of HuR is associated with increased COX-2 expression in some cancers. The aim of this study was to investigate the correlation between COX-2 and HuR in Ewing sarcoma.
Methods
The expression patterns for HuR and COX-2 were assessed via immunochemical analysis of 70 Ewing sarcoma samples.
Results
Nuclear HuR expression was observed in 12 of 70 (17.1%) cases, but cytoplasmic expression was not observed. COX-2 expression was seen in 25 of 70 (35.7%) samples. Nuclear HuR and COX-2 were simultaneously expressed in 8 of 70 (11.4%) samples. The expression of nuclear HuR was significantly associated with COX-2 expression (P = 0.014). Neither HuR nor COX-2 expression showed a correlation with age or sex.
Conclusions
COX-2 expression in Ewing sarcoma may not be directly related to mRNA stabilization by HuR. However, a correlation between COX-2 expression and nuclear HuR expression through indirect mRNA stabilization can be suggested.
GoodP.J.: The role of elav-like genes, a conserved family encoding RNA-binding proteins, in growth and development.Semin Cell Dev Biol, 8: 577–584, 1997.
2.
ChenC.Y., ShyuA.B.: AU-rich elements: characterization and importance in mRNA degradation.Trends Biochem Sci, 20: 465–470, 1995.
3.
BrennanC.M., SteitzJ.A.: HuR and mRNA stability.Cell Mol Life Sci, 58: 266–277, 2001.
4.
BarreauC., PaillardL., OsborneH.B.: AU-rich elements and associated factors: are there unifying principles?Nucleic Acids Res,33: 7138–7150, 2005.
5.
NagaokaK., SuzukiT., KawanoT., ImakawaK., SakaiS.: Stability of casein mRNA is ensured by structural interactions between the 3‘-untranslated region and poly(A) tail via the HuR and poly(A)-binding protein complex.Biochim Biophys Acta, 1759: 132–140, 2006.
6.
WangW., CaldwellM.C., LinS., FurneauxH., GorospeM.: HuR regulates cyclin A and cyclin B1 mRNA stability during cell proliferation.Embo J, 19: 2340–2350, 2000.
7.
WeinG., RosslerM., KlugR., HergetT.: The 3‘-UTR of the mRNA coding for the major protein kinase C substrate MAR-CKS contains a novel CU-rich element interacting with the mRNA stabilizing factors HuD and HuR.Eur J Biochem, 270: 350–365, 2003.
8.
KawaiT., LalA., YangX., GalbanS., Mazan-MamczarzK., GorospeM.: Translational control of cytochrome c by RNA-binding proteins TIA-1 and HuR.Mol Cell Biol, 26: 3295–3307, 2006.
9.
MaW.J., ChengS., CampbellC., WrightA., FurneauxH.: Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein.J Biol Chem, 271: 8144–8151, 1996.
10.
CipolloneF., FaziaM.L.: COX-2 and atherosclerosis.J Cardiovasc Pharmacol,47(Suppl 1): S26–36, 2006.
11.
MannJ.R., BacklundM.G., DuBoisR.N.: Mechanisms of disease: Inflammatory mediators and cancer prevention.Nat Clin Pract Oncol, 2: 202–210, 2005.
12.
TatsuguchiA., MatsuiK., ShinjiY., GudisK., TsukuiT., KishidaT., FukudaY., SugisakiY., TokunagaA., TajiriT., SakamotoC.: Cyclooxygenase-2 expression correlates with angiogenesis and apoptosis in gastric cancer tissue.Hum Pathol, 35: 488–495, 2004.
13.
TsujiiM., KawanoS., DuBoisR.N.: Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential.Proc Natl Acad Sci USA, 94: 3336–3340, 1997.
14.
TsujiiM., KawanoS., TsujiS., SawaokaH., HoriM., DuBoisR.N.: Cyclooxygenase regulates angiogenesis induced by colon cancer cells.Cell, 93: 705–716, 1998.
15.
KakiuchiY., TsujiS., TsujiiM., MurataH., KawaiN., YasumaruM., KimuraA., KomoriM., IrieT., MiyoshiE., SasakiY., HayashiN., KawanoS., HoriM.: Cyclooxygenase-2 activity altered the cell-surface carbohydrate antigens on colon cancer cells and enhanced liver metastasis.Cancer Res, 62: 1567–1572, 2002.
16.
ZerkowskiM.P., CampR.L., BurtnessB.A., RimmD.L., ChungG.G.: Quantitative analysis of breast cancer tissue microarrays shows high cox-2 expression is associated with poor outcome.Cancer Invest, 25: 19–26, 2007.
17.
EndoM., MatsumuraT., YamaguchiT., YamaguchiU., MorimotoY., NakataniF., KawaiA., ChumanH., BeppuY., ShimodaT., HasegawaT.: Cyclooxygenase-2 overexpression associated with a poor prognosis in chondrosarcomas.Hum Pathol, 37: 471–476, 2006.
DenkertC., WinzerK.J., MullerB.M., WeichertW., PestS., KobelM., KristiansenG., RelesA., SiegertA., GuskiH., HauptmannS.: Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma.Cancer, 97: 2978–2987, 2003.
20.
FanX.C., SteitzJ.A.: Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs.Embo J, 17: 3448–3460, 1998.
21.
DenkertC., WeichertW., PestS., KochI., LichtD., KobelM., RelesA., SehouliJ., DietelM., HauptmannS.: 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, 64: 189–195, 2004.
22.
DenkertC., KochI., von KeyserlingkN., NoskeA., NiesporekS., DietelM., WeichertW.: Expression of the ELAV-like protein HuR in human colon cancer: association with tumor stage and cyclooxygenase-2.Mod Pathol, 19: 1261–1269, 2006.
23.
DenkertC., WeichertW., WinzerK.J., MullerB.M., NoskeA., NiesporekS., KristiansenG., GuskiH., DietelM., HauptmannS.: 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, 10: 5580–5586, 2004.
24.
ErkinheimoT.L., LassusH., SivulaA., SenguptaS., FurneauxH., HlaT., HaglundC., ButzowR., RistimakiA.: Cytoplasmic HuR expression correlates with poor outcome and with cyclooxygenase 2 expression in serous ovarian carcinoma.Cancer Res, 63: 7591–7594, 2003.
25.
DickensD.S., KozielskiR., LeaveyP.J., TimmonsC., CripeT.P.: Cyclooxygenase-2 expression does not correlate with outcome in osteosarcoma or rhabdomyosarcoma.J Pediatr Hematol Oncol, 25: 282–285, 2003.
AtasoyU., WatsonJ., PatelD., KeeneJ.D.: ELAV protein HuA (HuR) can redistribute between nucleus and cytoplasm and is upregulated during serum stimulation and T cell activation.J Cell Sci, 111: 3145–3156, 1998.
28.
FanX.C., SteitzJ.A.: HNS, a nuclear-cytoplasmic shuttling sequence in HuR.Proc Natl Acad Sci USA, 95: 15293–15298, 1998.
