The online version of this article (doi:10.1186/1471-230X-14-9) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
MFL, RC, RRB and MACS conceived and designed the experiments. MFL was involved in literature search, genetic and statistical analysis. TKFM, PDRC and MCM were involved in immunohistochemistry analysis. MFL and DQC were involved in data collection. SD was responsible for pathology analysis. PPA was responsible by samples collection. MFL wrote the first draft of the manuscript. All authors listed have contributed to all subsequent drafts, and have approved the final manuscript.
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.
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.
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).
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.
Leal MF, Chung J, Calcagno DQ, Assumpcao PP, Demachki S, da Silva ID, Chammas R, Burbano RR, de Arruda Cardoso Smith M: Differential proteomic analysis of noncardia gastric cancer from individuals of northern Brazil. PLoS One. 2012, 7 (7): e42255-10.1371/journal.pone.0042255. CrossRefPubMedPubMedCentral
Okuwaki M, Tsujimoto M, Nagata K: The RNA binding activity of a ribosome biogenesis factor, nucleophosmin/B23, is modulated by phosphorylation with a cell cycle-dependent kinase and by association with its subtype. Mol Biol Cell. 2002, 13 (6): 2016-2030. 10.1091/mbc.02-03-0036. CrossRefPubMedPubMedCentral
Gimenez M, Souza VC, Izumi C, Barbieri MR, Chammas R, Oba-Shinjo SM, Uno M, Marie SK, Rosa JC: Proteomic analysis of low- to high-grade astrocytomas reveals an alteration of the expression level of raf kinase inhibitor protein and nucleophosmin. Proteomics. 2010, 10 (15): 2812-2821. 10.1002/pmic.200900722. CrossRefPubMed
Skaar TC, Prasad SC, Sharareh S, Lippman ME, Brunner N, Clarke R: Two-dimensional gel electrophoresis analyses identify nucleophosmin as an estrogen regulated protein associated with acquired estrogen-independence in human breast cancer cells. J Steroid Biochem Mol Biol. 1998, 67 (5–6): 391-402. CrossRefPubMed
Zeller KI, Haggerty TJ, Barrett JF, Guo Q, Wonsey DR, Dang CV: Characterization of nucleophosmin (B23) as a Myc target by scanning chromatin immunoprecipitation. J Biol Chem. 2001, 276 (51): 48285-48291. PubMed
Tanaka M, Sasaki H, Kino I, Sugimura T, Terada M: Genes preferentially expressed in embryo stomach are predominantly expressed in gastric cancer. Cancer Res. 1992, 52 (12): 3372-3377. PubMed
Lauren P: The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. an attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965, 64: 31-49. PubMed
Sobin LH, Gopodarowicz MK, Wittekind C: TNM Classification of Malignant Tumors. 2009, Oxford: Wiley-Blackwell, 7
Lobo Gatti L, Agostinho Jn F, De Labio R, Balbo Piason F, Carlos Da Silva L, Fagundez De Queiroz V, Peres CA, Barbieri D, De Arruda Cardoso Smith M, Marques Payao SL: Helicobacter pylori and cagA and vacA gene status in children from Brazil with chronic gastritis. Clin Exp Med. 2003, 3 (3): 166-172. 10.1007/s10238-003-0021-0. CrossRefPubMed
Karhemo PR, Rivinoja A, Lundin J, Hyvonen M, Chernenko A, Lammi J, Sihto H, Lundin M, Heikkila P, Joensuu H, et al: An extensive tumor array analysis supports tumor suppressive role for nucleophosmin in breast cancer. Am J Pathol. 2011, 179 (2): 1004-1014. 10.1016/j.ajpath.2011.04.009. CrossRefPubMedPubMedCentral
Assumpcao PP, Ishak G, Chen ES, Takeno SS, Leal MF, Guimaraes AC, Calcagno DQ, Khayat AS, Demachki S, Smith Mde A, et al: Numerical aberrations of chromosome 8 detected by conventional cytogenetics and fluorescence in situ hybridization in individuals from northern Brazil with gastric adenocarcinoma. Cancer Genet Cytogenet. 2006, 169 (1): 45-49. 10.1016/j.cancergencyto.2006.03.019. CrossRefPubMed
Burbano RR, Assumpcao PP, Leal MF, Calcagno DQ, Guimaraes AC, Khayat AS, Takeno SS, Chen ES, De Arruda Cardoso SM: C-MYC locus amplification as metastasis predictor in intestinal-type gastric adenocarcinomas: CGH study in Brazil. Anticancer Res. 2006, 26 (4B): 2909-2914. PubMed
Calcagno DQ, Guimaraes AC, Leal MF, Seabra AD, Khayat AS, Pontes TB, Assumpcao PP, De Arruda Cardoso SM, Burbano RR: MYC insertions in diffuse-type gastric adenocarcinoma. Anticancer Res. 2009, 29 (7): 2479-2483. PubMed
Calcagno DQ, Leal MF, Demachki S, Araujo MT, Freitas FW, Oliveira e Souza D, Assumpcao PP, Ishak G, de Arruda Cardoso Smith M, Burbano RR: MYC in gastric carcinoma and intestinal metaplasia of young adults. Cancer Genet Cytogenet. 2010, 202 (1): 63-66. 10.1016/j.cancergencyto.2010.05.020. CrossRefPubMed
Calcagno DQ, Leal MF, Seabra AD, Khayat AS, Chen ES, Demachki S, Assumpcao PP, Faria MH, Rabenhorst SH, Ferreira MV, et al: Interrelationship between chromosome 8 aneuploidy, C-MYC amplification and increased expression in individuals from northern Brazil with gastric adenocarcinoma. World J Gastroenterol. 2006, 12 (38): 6207-6211. CrossRefPubMedPubMedCentral
Calcagno DQ, Leal MF, Taken SS, Assumpcao PP, Demachki S, Smith Mde A, Burbano RR: Aneuploidy of chromosome 8 and C-MYC amplification in individuals from northern Brazil with gastric adenocarcinoma. Anticancer Res. 2005, 25 (6B): 4069-4074. PubMed
Costa Raiol LC, Figueira Silva EC, Mendes Da Fonseca D, Leal MF, Guimaraes AC, Calcagno DQ, Khayat AS, Assumpcao PP, De Arruda Cardoso Smith M, Burbano RR: Interrelationship between MYC gene numerical aberrations and protein expression in individuals from northern Brazil with early gastric adenocarcinoma. Cancer Genet Cytogenet. 2008, 181 (1): 31-35. 10.1016/j.cancergencyto.2007.10.011. CrossRefPubMed
Rosal-Texeira C, Leal MF, Calcagno DQ, Sozinho EKC, Borges BN, Montenegro RC, Santos AKR, Santos SEB, Ribeiro HF, Assumpção PP, et al: MYC deregulation in gastric cancer and its clinicopathological implications. PLoS One. 2013, in press
de Sousa AR, Penalva LO, Marcotte EM, Vogel C: Global signatures of protein and mRNA expression levels. Mol Biosyst. 2009, 5 (12): 1512-1526.
Tahara E: Genetic pathways of two types of gastric cancer. IARC Sci Publ. 2004, 157: 327-349. PubMed
- Deregulated expression of Nucleophosmin 1 in gastric cancer and its clinicopathological implications
Mariana Ferreira Leal
Tatianee Katsue Furuya Mazzotti
Danielle Queiroz Calcagno
Priscilae Daniele Ramos Cirilo
Margarita Cortes Martinez
Paulo Pimentel Assumpção
Rommel Rodríguez Burbano
Marília Cardoso Smith
- BioMed Central
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