title: RanGTPase: a candidate for Myc-mediated cancer progression.
abstract: BACKGROUND
  Ras-related nuclear protein (Ran) is required for cancer cell survival in vitro and human cancer progression, but the molecular mechanisms are largely unknown.
  
  
  METHODS
  We investigated the effect of the v-myc myelocytomatosis viral oncogene homolog (Myc) on Ran expression by Western blot, chromatin immunoprecipitation, and luciferase reporter assays and the effects of Myc and Ran expression in cancer cells by soft-agar, cell adhesion, and invasion assays. The correlation between Myc and Ran and the association with patient survival were investigated in 14 independent patient cohorts (n = 2430) and analyzed with Spearman's rank correlation and Kaplan-Meier plots coupled with Wilcoxon-Gehan tests, respectively. All statistical tests were two-sided.
  
  
  RESULTS
  Myc binds to the upstream sequence of Ran and transactivates Ran promoter activity. Overexpression of Myc upregulates Ran expression, whereas knockdown of Myc downregulates Ran expression. Myc or Ran overexpression in breast cancer cells is associated with cancer progression and metastasis. Knockdown of Ran reverses the effect induced by Myc overexpression in breast cancer cells. In clinical data, a positive association between Myc and Ran expression was revealed in 288 breast cancer and 102 lung cancer specimens. Moreover, Ran expression levels differentiate better or poorer survival in Myc overexpressing breast (χ2 = 24.1; relative risk [RR] = 9.1, 95% confidence interval [CI] = 3.3 to 24.7, P < .001) and lung (χ2 = 6.04; RR = 2.8, 95% CI = 1.2 to 6.3; P = .01) cancer cohorts.
  
  
  CONCLUSIONS
  Our results suggest that Ran is required for and is a potential therapeutic target of Myc-driven cancer progression in both breast and lung cancers.
authors.affiliation: Center for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, BT9 7BL, UK.
authors.forename: Hiu-Fung
authors.initials: HF
authors.lastname: Yuen
authors.forename: Vignesh-Kumar
authors.initials: VK
authors.lastname: Gunasekharan
authors.forename: Ka-Kui
authors.initials: KK
authors.lastname: Chan
authors.forename: Shu-Dong
authors.initials: SD
authors.lastname: Zhang
authors.forename: Angela
authors.initials: A
authors.lastname: Platt-Higgins
authors.forename: Kathy
authors.initials: K
authors.lastname: Gately
authors.forename: Ken
authors.initials: K
authors.lastname: O'Byrne
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fennell
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Johnston
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rudland
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Tanani
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016259:Genes, myc; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010957:Plasmids; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D020931:ran GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C120587:RAN protein, human; D020558:GTP Phosphohydrolases; D020931:ran GTP-Binding Protein