title: Methyl(R217)HuR and MCM6 are inversely correlated and are prognostic markers in non small cell lung carcinoma.
abstract: OBJECTIVE
  In non small cell lung carcinoma (NSCLC), earlier studies supported a prognostic value of intra-cytoplasmic HuR expression. HuR is a RNA binding protein previously shown to stimulate proliferation, but the link between HuR and proliferation in NSCLC has not yet been evaluated. The first objective of this study was to analyze the expression of HuR in a series of NSCLC and to correlate this to two proliferation markers, Ki-67 and MCM6. As potential post-transcriptional regulatory mechanisms for HuR expression, two miRNAs, miR16 and miR519, were also analyzed. Finally, because HuR methylation could be involved in its nucleocytoplasmic shuttling, the expression of methyl(R217)HuR and its relation to cancer survival were determined.
  
  
  METHODS
  Immunohistochemistry was used to evaluate the expression of HuR, methy(R217)HuR, Ki-67 and MCM6 in a series of 190 NSCLCs. The level of miR16 and miR519 was determined by qRT-PCR.
  
  
  RESULTS
  Higher cytoplasmic HuR staining was found in tumor vs. control paired normal lung (p<0.0001), but without correlation with survival. The level of methyl(R217)HuR was correlated both significantly with intra-cytoplasmic HuR staining (p<0.001), and overall survival (p=0.01). MCM6 correlated to a poorer overall survival (p<0.01). Both MCM6 and Ki-67 were positively correlated with HuR nuclear staining (p<0.0001 and p<0.001, respectively). On the contrary, MCM6 and Ki-67 correlated inversely to methyl(R217)HuR (p<0.001 and p=0.01, respectively). The levels of miR16 and miR519 were significantly lower in tumor tissue vs. paired normal lung (p<0.0001), but only miR519 correlated inversely to HuR expression (p=0.01).
  
  
  CONCLUSIONS
  While overall cytoplasmic HuR level was higher in tumor tissues, we found unexpectedly that methyl(R217)HuR was a marker of good prognosis. Furthermore, our data suggest that HuR level could be regulated by miR519. Finally, we demonstrated that Ki-67 and MCM6, both correlated with HuR, are valuable markers of poor prognosis in NSCLC.
authors.affiliation: Department of Pathology, CHU Nancy, France.
authors.forename: Charlène
authors.initials: C
authors.lastname: Vigouroux
authors.affiliation: Department of Pathology, CHU Nancy, France; INSERM U954, Faculty of Medicine, Université de Lorraine, Nancy, France.
authors.forename: Jean-Matthieu
authors.initials: JM
authors.lastname: Casse
authors.affiliation: INSERM U954, Faculty of Medicine, Université de Lorraine, Nancy, France; Department of Molecular Biology and Biochemistry, CHU Nancy, France.
authors.forename: Shyue-Fang
authors.initials: SF
authors.lastname: Battaglia-Hsu
authors.affiliation: Department of Pathology, CHU Nancy, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Brochin
authors.affiliation: INGRES, EA7298, Faculty of Medicine, Université de Lorraine, Nancy, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Luc
authors.affiliation: INGRES, EA7298, Faculty of Medicine, Université de Lorraine, Nancy, France; Department of Occupational Diseases, CHU Nancy, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Paris
authors.affiliation: Centre de Ressources Biologiques, BB-0033-00035, CHU Nancy, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lacomme
authors.affiliation: INSERM U954, Faculty of Medicine, Université de Lorraine, Nancy, France; Department of Molecular Biology and Biochemistry, CHU Nancy, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Gueant
authors.affiliation: Department of Pathology, CHU Nancy, France; INSERM U954, Faculty of Medicine, Université de Lorraine, Nancy, France; Centre de Ressources Biologiques, BB-0033-00035, CHU Nancy, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vignaud
authors.affiliation: Department of Pathology, CHU Nancy, France; INSERM U954, Faculty of Medicine, Université de Lorraine, Nancy, France. Electronic address: g.gauchotte@chu-nancy.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gauchotte
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008745:Methylation; D008875:Middle Aged; D064151:Minichromosome Maintenance Complex Component 6 / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D021381:Protein Transport
chemical_list: D014408:Biomarkers, Tumor; D000067780:ELAV-Like Protein 1; D064151:Minichromosome Maintenance Complex Component 6
keywords: HuR; Ki-67; Lung cancer; MCM6; miR16; miR519