title: Altered subcellular localization of suppressin, a novel inhibitor of cell-cycle entry, is an independent prognostic factor in colorectal adenocarcinomas.
abstract: OBJECTIVE
  Suppressin (SPN), a novel inhibitor of the entry into the cell cycle, has properties of a tumor suppressor gene; however, its role in the development and progression of a human malignancy is not studied. Therefore, we evaluated the status of spn and its prognostic value in human colorectal adenocarcinoma (CRC).
  
  
  METHODS
  Inhibition of cell proliferation by exogenous/extracellular SPN was assessed by [(3)H]thymidine incorporation. The genetic status of spn in two colon cancer cell lines (LS180 and WiDr) and in a human CRC was determined using direct cDNA sequencing techniques. Phenotypic expression of SPN was evaluated in 105 CRC archival tissues using immunohistochemical methods. Univariate Kaplan-Meier and multivariate Cox proportional hazards models were used to determine the prognostic significance of SPN expression.
  
  
  RESULTS
  Exogenous SPN inhibited the proliferation of the LS180 cell line, which also has a mutation in one allele of the spn gene. The spn gene was also mutated in the primary CRC. Expression of SPN was primarily cytoplasmic in nonmucinous CRCs and nuclear in mucinous CRCs. However, the evaluation of 85 nonmucinous CRCs demonstrated that nuclear localization of SPN, nuclear accumulation of p53, and nodal status were independent prognostic indicators with hazard ratios of 2.34, 2.33, and 3.04, respectively. Nuclear localization of SPN plus nuclear accumulation of p53 formed a stronger prognostic indicator (hazard ratios = 5.45) than local nodal status.
  
  
  CONCLUSIONS
  This is the first report of genetic alterations in the spn gene in a human malignancy and suggests that genetic alterations in spn and the resulting immunohistochemical phenotypes based on SPN subcellular localization in CRCs may be useful in determining prognosis of patients with subtypes of CRC.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. manne@oath.uab.edu
authors.forename: U
authors.initials: U
authors.lastname: Manne
authors.forename: B D
authors.initials: BD
authors.lastname: Gary
authors.forename: D K
authors.initials: DK
authors.lastname: Oelschlager
authors.forename: H L
authors.initials: HL
authors.lastname: Weiss
authors.forename: A R
authors.initials: AR
authors.lastname: Frost
authors.forename: W E
authors.initials: WE
authors.lastname: Grizzle
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003593:Cytoplasm / Q000378:metabolism; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D009154:Mutation; D011379:Prognosis; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D013951:Thymus Hormones / Q000032:analysis / Q000235:genetics* / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D013951:Thymus Hormones; D016159:Tumor Suppressor Protein p53; C053750:suppressin