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BMC Gastroenterology
Published in: BMC Gastroenterology 1/2014

Open Access 01-12-2014 | Research article

Deregulated expression of Nucleophosmin 1 in gastric cancer and its clinicopathological implications

Authors: Mariana Ferreira Leal, Tatianee Katsue Furuya Mazzotti, Danielle Queiroz Calcagno, Priscilae Daniele Ramos Cirilo, Margarita Cortes Martinez, Samia Demachki, Paulo Pimentel Assumpção, Roger Chammas, Rommel Rodríguez Burbano, Marília Cardoso Smith

Published in: BMC Gastroenterology | Issue 1/2014

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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).

Conclusion

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.
Appendix
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Literature
1.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61 (2): 69-90. 10.3322/caac.20107.CrossRefPubMed
2.
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
3.
Grisendi S, Mecucci C, Falini B, Pandolfi PP: Nucleophosmin and cancer. Nat Rev Cancer. 2006, 6 (7): 493-505. 10.1038/nrc1885.CrossRefPubMed
4.
5.
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
6.
Okuda M: The role of nucleophosmin in centrosome duplication. Oncogene. 2002, 21 (40): 6170-6174. 10.1038/sj.onc.1205708.CrossRefPubMed
7.
Tarapore P, Okuda M, Fukasawa K: A mammalian in vitro centriole duplication system: evidence for involvement of CDK2/cyclin E and nucleophosmin/B23 in centrosome duplication. Cell Cycle. 2002, 1 (1): 75-81.CrossRefPubMed
8.
Grisendi S, Bernardi R, Rossi M, Cheng K, Khandker L, Manova K, Pandolfi PP: Role of nucleophosmin in embryonic development and tumorigenesis. Nature. 2005, 437 (7055): 147-153. 10.1038/nature03915.CrossRefPubMed
9.
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
10.
Nozawa Y, Van Belzen N, Van der Made AC, Dinjens WN, Bosman FT: Expression of nucleophosmin/B23 in normal and neoplastic colorectal mucosa. J Pathol. 1996, 178 (1): 48-52. 10.1002/(SICI)1096-9896(199601)178:1<48::AID-PATH432>3.0.CO;2-Y.CrossRefPubMed
11.
Yun JP, Miao J, Chen GG, Tian QH, Zhang CQ, Xiang J, Fu J, Lai PB: Increased expression of nucleophosmin/B23 in hepatocellular carcinoma and correlation with clinicopathological parameters. Br J Cancer. 2007, 96 (3): 477-484. 10.1038/sj.bjc.6603574.CrossRefPubMedPubMedCentral
12.
Tsui KH, Cheng AJ, Chang PL, Pan TL, Yung BY: Association of nucleophosmin/B23 mRNA expression with clinical outcome in patients with bladder carcinoma. Urology. 2004, 64 (4): 839-844. 10.1016/j.urology.2004.05.020.CrossRefPubMed
13.
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
14.
Shields LB, Gercel-Taylor C, Yashar CM, Wan TC, Katsanis WA, Spinnato JA, Taylor DD: Induction of immune responses to ovarian tumor antigens by multiparity. J Soc Gynecol Investig. 1997, 4 (6): 298-304. 10.1016/S1071-5576(97)00068-3.CrossRefPubMed
15.
Subong EN, Shue MJ, Epstein JI, Briggman JV, Chan PK, Partin AW: Monoclonal antibody to prostate cancer nuclear matrix protein (PRO:4-216) recognizes nucleophosmin/B23. Prostate. 1999, 39 (4): 298-304. 10.1002/(SICI)1097-0045(19990601)39:4<298::AID-PROS11>3.0.CO;2-M.CrossRefPubMed
16.
Qian Z, Joslin JM, Tennant TR, Reshmi SC, Young DJ, Stoddart A, Larson RA, Le Beau MM: Cytogenetic and genetic pathways in therapy-related acute myeloid leukemia. Chem Biol Interact. 2010, 184 (1–2): 50-57.CrossRefPubMed
17.
Naoe T, Suzuki T, Kiyoi H, Urano T: Nucleophosmin: a versatile molecule associated with hematological malignancies. Cancer Sci. 2006, 97 (10): 963-969. 10.1111/j.1349-7006.2006.00270.x.CrossRefPubMed
18.
Mendes-da-Silva P, Moreira A, Duro-da-Costa J, Matias D, Monteiro C: Frequent loss of heterozygosity on chromosome 5 in non-small cell lung carcinoma. Mol Pathol. 2000, 53 (4): 184-187. 10.1136/mp.53.4.184.CrossRefPubMedPubMedCentral
19.
Falini B, Martelli MP, Bolli N, Sportoletti P, Liso A, Tiacci E, Haferlach T: Acute myeloid leukemia with mutated nucleophosmin (NPM1): is it a distinct entity?. Blood. 2011, 117 (4): 1109-1120. 10.1182/blood-2010-08-299990.CrossRefPubMed
20.
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
21.
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
22.
You BJ, Huang IJ, Liu WH, Hung YB, Chang JH, Yung BY: Decrease in nucleophosmin/B23 mRNA and telomerase activity during indomethacin-induced apoptosis of gastric KATO-III cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 1999, 360 (6): 683-690. 10.1007/s002109900145.CrossRefPubMed
23.
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
24.
Sobin LH, Gopodarowicz MK, Wittekind C: TNM Classification of Malignant Tumors. 2009, Oxford: Wiley-Blackwell, 7
25.
Clayton CL, Kleanthous H, Coates PJ, Morgan DD, Tabaqchali S: Sensitive detection of Helicobacter pylori by using polymerase chain reaction. J Clin Microbiol. 1992, 30 (1): 192-200.PubMedPubMedCentral
26.
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
27.
28.
Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ: Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell. 1997, 91 (5): 649-659. 10.1016/S0092-8674(00)80452-3.CrossRefPubMed
29.
Kuo ML, den Besten W, Bertwistle D, Roussel MF, Sherr CJ: N-terminal polyubiquitination and degradation of the Arf tumor suppressor. Genes Dev. 2004, 18 (15): 1862-1874. 10.1101/gad.1213904.CrossRefPubMedPubMedCentral
30.
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
31.
Liu Y, Zhang F, Zhang XF, Qi LS, Yang L, Guo H, Zhang N: Expression of nucleophosmin/NPM1 correlates with migration and invasiveness of colon cancer cells. J Biomed Sci. 2012, 19: 53-10.1186/1423-0127-19-53.CrossRefPubMedPubMedCentral
32.
Bonetti P, Davoli T, Sironi C, Amati B, Pelicci PG, Colombo E: Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7 gamma. J Cell Biol. 2008, 182 (1): 19-26. 10.1083/jcb.200711040.CrossRefPubMedPubMedCentral
33.
Calcagno DQ, Leal MF, Assumpcao PP, Smith MA, Burbano RR: MYC and gastric adenocarcinoma carcinogenesis. World J Gastroenterol. 2008, 14 (39): 5962-5968. 10.3748/wjg.14.5962.CrossRefPubMedPubMedCentral
34.
Leal MF, Calcagno DQ, Khayat AS, Silva TC, Muniz JA, Assumpcao PP, de Arruda Cardoso Smith M, Burbano RR: hTERT and TP53 deregulation in intestinal-type gastric carcinogenesis in non-human primates. Clin Exp Med. 2013, 13 (3): 221-224. 10.1007/s10238-012-0195-4.CrossRefPubMed
35.
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
36.
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
37.
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
38.
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
39.
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
40.
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
41.
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
42.
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
43.
Lindstrom MS: NPM1/B23: a multifunctional chaperone in ribosome biogenesis and chromatin remodeling. Biochem Res Int. 2011, 2011: 195209-CrossRefPubMed
44.
Nawa Y, Kawahara K, Tancharoen S, Meng X, Sameshima H, Ito T, Masuda Y, Imaizumi H, Hashiguchi T, Maruyama I: Nucleophosmin may act as an alarmin: implications for severe sepsis. J Leukoc Biol. 2009, 86 (3): 645-653. 10.1189/jlb.1008644.CrossRefPubMed
45.
Guery L, Benikhlef N, Gautier T, Paul C, Jego G, Dufour E, Jacquel A, Cally R, Manoury B, Vanden Berghe T, et al: Fine-tuning nucleophosmin in macrophage differentiation and activation. Blood. 2011, 118 (17): 4694-4704. 10.1182/blood-2011-03-341255.CrossRefPubMedPubMedCentral
46.
Enomoto T, Lindstrom MS, Jin A, Ke H, Zhang Y: Essential role of the B23/NPM core domain in regulating ARF binding and B23 stability. J Biol Chem. 2006, 281 (27): 18463-18472. 10.1074/jbc.M602788200.CrossRefPubMed
47.
Itahana K, Bhat KP, Jin A, Itahana Y, Hawke D, Kobayashi R, Zhang Y: Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Mol Cell. 2003, 12 (5): 1151-1164. 10.1016/S1097-2765(03)00431-3.CrossRefPubMed
48.
Endo A, Matsumoto M, Inada T, Yamamoto A, Nakayama KI, Kitamura N, Komada M: Nucleolar structure and function are regulated by the deubiquitylating enzyme USP36. J Cell Sci. 2009, 122 (Pt 5): 678-686.CrossRefPubMed
49.
Sato K, Hayami R, Wu W, Nishikawa T, Nishikawa H, Okuda Y, Ogata H, Fukuda M, Ohta T: Nucleophosmin/B23 is a candidate substrate for the BRCA1-BARD1 ubiquitin ligase. J Biol Chem. 2004, 279 (30): 30919-30922. 10.1074/jbc.C400169200.CrossRefPubMed
50.
Laurent JM, Vogel C, Kwon T, Craig SA, Boutz DR, Huse HK, Nozue K, Walia H, Whiteley M, Ronald PC, et al: Protein abundances are more conserved than mRNA abundances across diverse taxa. Proteomics. 2010, 10 (23): 4209-4212. 10.1002/pmic.201000327.CrossRefPubMedPubMedCentral
51.
Lu P, Vogel C, Wang R, Yao X, Marcotte EM: Absolute protein expression profiling estimates the relative contributions of transcriptional and translational regulation. Nat Biotechnol. 2007, 25 (1): 117-124. 10.1038/nbt1270.CrossRefPubMed
52.
Anderson L, Seilhamer J: A comparison of selected mRNA and protein abundances in human liver. Electrophoresis. 1997, 18 (3–4): 533-537.CrossRefPubMed
53.
de Sousa AR, Penalva LO, Marcotte EM, Vogel C: Global signatures of protein and mRNA expression levels. Mol Biosyst. 2009, 5 (12): 1512-1526.
54.
Raj A, Peskin CS, Tranchina D, Vargas DY, Tyagi S: Stochastic mRNA synthesis in mammalian cells. PLoS Biol. 2006, 4 (10): e309-10.1371/journal.pbio.0040309.CrossRefPubMedPubMedCentral
55.
Tahara E: Genetic pathways of two types of gastric cancer. IARC Sci Publ. 2004, 157: 327-349.PubMed
Metadata
Title
Deregulated expression of Nucleophosmin 1 in gastric cancer and its clinicopathological implications
Authors
Mariana Ferreira Leal
Tatianee Katsue Furuya Mazzotti
Danielle Queiroz Calcagno
Priscilae Daniele Ramos Cirilo
Margarita Cortes Martinez
Samia Demachki
Paulo Pimentel Assumpção
Roger Chammas
Rommel Rodríguez Burbano
Marília Cardoso Smith
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Gastroenterology / Issue 1/2014
Electronic ISSN: 1471-230X
DOI
https://doi.org/10.1186/1471-230X-14-9

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