title: Deregulated expression of Nucleophosmin 1 in gastric cancer and its clinicopathological implications.
abstract: BACKGROUND
  The process of gastric carcinogenesis still remains to be elucidated. The identification of genes related to this process may help to reduce mortality rates through early diagnosis and the development of new anticancer therapies. Nucleophosmin 1 (NPM1) acts in ribosome biogenesis, centrosome duplication, maintenance of genomic stability, and embryonic development. Recently, NPM1 has been implicated in the tumorigenesis processes. Here, we evaluated NPM1 gene and protein expression in gastric tumors and in corresponding non-neoplastic gastric samples.
  
  
  METHODS
  NPM1 protein expression was determined by Western blot in 17 pairs of gastric tumors and corresponding non-neoplastic gastric tissue. The protein immunoreactivity was observed in 12 tumor samples. mRNA expression was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in 22 pairs of gastric tumors and in matched non-neoplastic gastric tissue.
  
  
  RESULTS
  NPM1 protein expression was significantly reduced in gastric cancer samples compared to matched non-neoplastic gastric samples (P = 0.019). The protein level of NPM1 was reduced at least 1.5-fold in 35% of tumors compared to paired non-neoplastic gastric tissue. However, NPM1 immunoreactivity was detected in neoplastic and non-neoplastic cells, including in intestinal metaplastic, gastritis and inflammatory cells. NPM1 was mainly expressed in nucleus and nucleolus subcellular compartments. The staining intensity and the percentage of immunoreactive cells varied among the studied cases. The NPM1 mRNA level was reduced at least 1.5-fold in 45.5% of samples and increased in 27.3% of samples. An inverse correlation between protein and mRNA expression was detected (r = -0.509, P = 0.037). Intestinal-type gastric cancer presented higher mRNA levels than diffuse-type (P = 0.026). However, reduced NPM1 protein expression was associated with intestinal-type gastric cancer compared to matched non-neoplastic gastric samples (P = 0.018). In addition, tumors from patients with known distant metastasis presented reduced NPM1 protein levels compared to tumors from patients without distant metastasis (P < 0.001).
  
  
  CONCLUSIONS
  Although the expression of NPM1 is heterogeneous in gastric tumors, our results suggest that NPM1 down-regulation may have a role in gastric carcinogenesis and may help in the selection of anticancer treatment strategies.
authors.affiliation: Genetics Division, Department of Morphology and Genetic, Federal University of São Paulo, R, Botucatu, 740, São Paulo, SP CEP 04023-900, Brazil. mariana.morf@epm.br.
authors.forename: Mariana Ferreira
authors.initials: MF
authors.lastname: Leal
authors.forename: Tatiane Katsue Furuya
authors.initials: TK
authors.lastname: Mazzotti
authors.forename: Danielle Queiroz
authors.initials: DQ
authors.lastname: Calcagno
authors.forename: Priscila Daniele Ramos
authors.initials: PD
authors.lastname: Cirilo
authors.forename: Margarita Cortes
authors.initials: MC
authors.lastname: Martinez
authors.forename: Samia
authors.initials: S
authors.lastname: Demachki
authors.forename: Paulo Pimentel
authors.initials: PP
authors.lastname: Assumpção
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.forename: Rommel Rodríguez
authors.initials: RR
authors.lastname: Burbano
authors.forename: Marília Cardoso
authors.initials: MC
authors.lastname: Smith
mesh_terms: D000328:Adult; D002466:Cell Nucleolus / Q000737:chemistry; D002467:Cell Nucleus / Q000737:chemistry; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology*; D005756:Gastritis / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008679:Metaplasia / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000090243:Nucleophosmin