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

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.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Dept Morphol & Genet, Div Genet, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Orthoped & Traumatol, BR-04038031 São Paulo, BrazilUniv São Paulo, Sch Med, Dept Radiol, Expt Oncol Lab, BR-01246903 São Paulo, BrazilSão Paulo State Canc Inst, Ctr Translat Oncol, BR-01246000 São Paulo, BrazilFed Univ Para, Joao de Barros Barreto Univ Hosp, Oncol Res Ctr, BR-60673000 Belem, Para, BrazilFed Univ Para, Inst Biol Sci, Human Cytogenet Lab, BR-66073000 Belem, Para, BrazilUniversidade Federal de São Paulo, Dept Morphol & Genet, Div Genet, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Orthoped & Traumatol, BR-04038031 São Paulo, BrazilWeb of Scienc

Prohibitin Expression Deregulation in Gastric Cancer Is Associated with the 3 ' Untranslated Region 1630 C > T Polymorphism and Copy Number Variation

PHB is a reported oncogene and tumor suppressor in gastric cancer. Here, we evaluated whether the PHB copy number and the rs6917 polymorphism affect its expression in gastric cancer. Down-regulation and up-regulation of PHB were observed in the evaluated tumors. Reduced expression was associated with tumor dedifferentiation and cancer initiation. the T allele of the rs6917 polymorphism was associated with reduced PHB mRNA levels. Moreover, the up-regulation of PHB appeared to be regulated by the gain of additional gene copies. Thus, PHB copy number variation and differential expression of the rs6917 polymorphism may play a role in PHB transcriptional regulation.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Universidade Federal de São Paulo, Disciplina Genet, Dept Morfol & Genet, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Ortopedia & Traumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Fac Med, Dept Radiol, Lab Oncol Expt, São Paulo, BrazilInst Canc Estado São Paulo, Ctr Invest Translat Oncol, São Paulo, BrazilFed Univ Para, Hosp Univ Joao Barros Barreto, BR-66059 Belem, Para, BrazilFed Univ Para, Inst Ciencias Biol, Lab Citogenet Humana, BR-66059 Belem, Para, BrazilUniversidade Federal de São Paulo, Disciplina Genet, Dept Morfol & Genet, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Ortopedia & Traumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Fac Med, Dept Radiol, Lab Oncol Expt, São Paulo, BrazilWeb of Scienc

Pigmento de titânio em tecidos de toxicômanos: relatos de cinco casos necropsiados

O objetivo deste relato é descrever os achados anatomopatológicos de cinco casos de toxicômanos com pigmento de titânio em vários órgãos, após injeção de comprimidos esmagados de cloridrato de propoxifeno. Foram obtidos fragmentos do fígado, baço, pulmões, linfonodos e medula óssea e, após a avaliação macroscópica, amostras foram submetidas à microscopia de luz comum e de luz polarizada. Em todos os cinco casos, foi encontrado um pigmento com características de dióxido de titânio nas amostras dos órgãos estudados. Nossos achados sugerem que a pesquisa sobre pigmento de titânio em tecidos corporais deva ser complementada, considerando-se a contribuição de dados morfológicos em Patologia Forense.The aim of this report is to describe the anatomic-pathologic findings from necropsies of 5 drug addicts with titanium pigment in several organs after chronic intravenous injection of crushed propoxyphene hydrochloride tablets. Samples from liver, spleen, lungs, lymph nodes, and bone marrow were obtained, and after being grossly studied, they were submitted to evaluation using common light and polarized microscopy. In all 5 cases, a pigment with characteristics of titanium dioxide was found within tissue samples of the organs studied. Our findings suggest that research concerning titanium pigment within body tissues should be enhanced, considering the potential contribution of this morphologic data to forensic pathology

MYC, FBXW7 and TP53 copy number variation and expression in Gastric Cancer

Background: MYC deregulation is a common event in gastric carcinogenesis, usually as a consequence of gene amplification, chromosomal translocations, or posttranslational mechanisms. FBXW7 is a p53-controlled tumor-suppressor that plays a role in the regulation of cell cycle exit and reentry via MYC degradation.Methods: We evaluated MYC, FBXW7, and TP53 copy number, mRNA levels, and protein expression in gastric cancer and paired non-neoplastic specimens from 33 patients and also in gastric adenocarcinoma cell lines. We also determined the invasion potential of the gastric cancer cell lines.Results: MYC amplification was observed in 51.5% of gastric tumor samples. Deletion of one copy of FBXW7 and TP53 was observed in 45.5% and 21.2% of gastric tumors, respectively. MYC mRNA expression was significantly higher in tumors than in non-neoplastic samples. FBXW7 and TP53 mRNA expression was markedly lower in tumors than in paired non-neoplastic specimens. Moreover, deregulated MYC and FBXW7 mRNA expression was associated with the presence of lymph node metastasis and tumor stage III-IV. Additionally, MYC immunostaining was more frequently observed in intestinal-type than diffuse-type gastric cancers and was associated with MYC mRNA expression. in vitro studies showed that increased MYC and reduced FBXW7 expression is associated with a more invasive phenotype in gastric cancer cell lines. This result encouraged us to investigate the activity of the gelatinases MMP-2 and MMP-9 in both cell lines. Both gelatinases are synthesized predominantly by stromal cells rather than cancer cells, and it has been proposed that both contribute to cancer progression. We observed a significant increase in MMP-9 activity in ACP02 compared with ACP03 cells. These results confirmed that ACP02 cells have greater invasion capability than ACP03 cells.Conclusion: in conclusion, FBXW7 and MYC mRNA may play a role in aggressive biologic behavior of gastric cancer cells and may be a useful indicator of poor prognosis. Furthermore, MYC is a candidate target for new therapies against gastric cancer.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fed Univ Para, Inst Ciencias Biol, Lab Citogenet Humana, BR-66059 Belem, Para, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Morfol & Genet, Disciplina Genet, BR-04023900 São Paulo, SP, BrazilUniv São Paulo, Inst Ciencias Biomed, Dept Biol Celular & Desenvolvimento, São Paulo, SP, BrazilFed Univ Para, Hosp Univ Joao Barros Barreto, Fac Med, Lab Imunoistoquim,Serv Anat Patol, BR-66059 Belem, PA, BrazilFed Univ Para, Hosp Univ Joao Barros Barreto, Serv Cirurgia, BR-66059 Belem, PA, BrazilFed Univ Para, Inst Ciencias Biol, Lab Genet Humana, BR-66059 Belem, PA, BrazilUniversidade Federal de São Paulo, Escola Paulista Med, Dept Morfol & Genet, Disciplina Genet, BR-04023900 São Paulo, SP, BrazilWeb of Scienc

Prognostic and Predictive Significance of MYC and KRAS Alterations in Breast Cancer from Women Treated with Neoadjuvant Chemotherapy

Breast cancer is a complex disease, with heterogeneous clinical evolution. Several analyses have been performed to identify the risk factors for breast cancer progression and the patients who respond best to a specific treatment. We aimed to evaluate whether the hormone receptor expression, HER2 and MYC genes and their protein status, and KRAS codon 12 mutations may be prognostic or predictive biomarkers of breast cancer. Protein, gene and mutation status were concomitantly evaluated in 116 breast tumors from women who underwent neoadjuvant chemotherapy with doxorubicin plus cyclophosphamide. We observed that MYC expression was associated with luminal B and HER2 overexpression phenotypes compared to luminal A (p= 2.5 was a protective factor for chemotherapy resistance. On the other hand, age and grade 2 tumors were a risk factor. Additionally, luminal B, HER2 overexpression, and triple-negative tumors presented increased odds of being resistant to chemotherapy relative to luminal A tumors. Thus, breast tumors with KRAS codon 12 mutations seem to present a worse prognosis. Additionally, MYC amplification may help in the identification of tumors that are sensitive to doxorubicin plus cyclophosphamide treatment. If confirmed in a large set of samples, these markers may be useful for clinical stratification and prognosis.Fundacao Amazonia Paraense de Amparo a PesquisaConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Ophir Loyola Hosp, Mastol Unit, Belem, PA, BrazilUniversidade Federal de São Paulo, Dept Orthopaed & Traumatol, São Paulo, BrazilFed Univ Para, Inst Biol Sci, Human Cytogenet Lab, BR-66059 Belem, PA, BrazilHosp Univ La Paz, Res Unit Unidad Invest, Madrid, SpainFed Univ Para, Nucleu Res Oncol, Joao de Barros Barreto Univ Hosp, BR-66059 Belem, PA, BrazilUniv Fed Piaui, Dept Biomed, Parnaiba, PI, BrazilUniversidade Federal de São Paulo, Div Genet, Dept Morphol & Genet, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Orthopaed & Traumatol, São Paulo, BrazilUniversidade Federal de São Paulo, Div Genet, Dept Morphol & Genet, São Paulo, BrazilFundacao Amazonia Paraense de Amparo a Pesquisa: FAPESPA/PPSUS 247/2009Fundacao Amazonia Paraense de Amparo a Pesquisa: 300240/2009Web of Scienc

Interrelationship between TP53 gene deletion, protein expression and chromosome 17 aneusomy in gastric adenocarcinoma

Background: This study evaluates the existence of numerical alterations of chromosome 17 and TP53 gene deletion in gastric adenocarcinoma. the p53 protein expression was also evaluated, as well as, possible associations with clinicopathological characteristics.Methods: Dual-color fluorescence in situ hybridization and immunostaining were performed in twenty gastric cancer samples of individuals from Northern Brazil.Results: Deletion of TP53 was found in all samples. TP53 was inactivated mainly by single allelic deletion, varying to 7-39% of cells/case. Aneusomy of chromosome 17 was observed in 85% of cases. Chromosome 17 monosomy and gain were both observed in about half of cases. Cells with gain of chromosome 17 frequently presented TP53 deletion. the frequency of cells with two chr17 and one TP53 signals observed was higher in diffuse than in intestinal-type GC. Immunoreactivity of p53 was found only in intestinal-type samples. the frequency of cells with two chr17 and two TP53 signals found was higher in samples with positive p53 expression than in negative cases in intestinal-type GC.Conclusion: We suggest that TP53 deletion and chromosome 17 aneusomy is a common event in GC and other TP53 alterations, as mutation, may be implicated in the distinct carcinogenesis process of diffuse and intestinal types.Financiadora de Estudos e Projetos (FINEP CT-INFRA/FADESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fed Univ Para, Inst Biol Sci, Humans Cytogenet Lab, BR-66075900 Belem, Para, BrazilUniv Fed Piaui, Dept Biol, Campus Minist Reis Velloso Parnaiba, Teresina, PI, BrazilUniversidade Federal de São Paulo, Dept Morphol, Div Genet, São Paulo, BrazilUniv Fed Ceara, Sch Med, Dept Pathol, Mol Genet Lab, Fortaleza, Ceara, BrazilFed Univ Para, Joao de Barros Barreto Univ Hosp, BR-66075900 Belem, Para, BrazilUniversidade Federal de São Paulo, Dept Morphol, Div Genet, São Paulo, BrazilFinanciadora de Estudos e Projetos (FINEP CT-INFRA/FADESP): 0927-03. RRBWeb of Scienc

MYC, FBXW7 and TP53 copy number variation and expression in Gastric Cancer

Abstract\ud \ud \ud \ud Background\ud MYC deregulation is a common event in gastric carcinogenesis, usually as a consequence of gene amplification, chromosomal translocations, or posttranslational mechanisms. FBXW7 is a p53-controlled tumor-suppressor that plays a role in the regulation of cell cycle exit and reentry via MYC degradation.\ud \ud \ud \ud Methods\ud We evaluated MYC, FBXW7, and TP53 copy number, mRNA levels, and protein expression in gastric cancer and paired non-neoplastic specimens from 33 patients and also in gastric adenocarcinoma cell lines. We also determined the invasion potential of the gastric cancer cell lines.\ud \ud \ud \ud Results\ud \ud MYC amplification was observed in 51.5% of gastric tumor samples. Deletion of one copy of FBXW7 and TP53 was observed in 45.5% and 21.2% of gastric tumors, respectively. MYC mRNA expression was significantly higher in tumors than in non-neoplastic samples. FBXW7 and TP53 mRNA expression was markedly lower in tumors than in paired non-neoplastic specimens. Moreover, deregulated MYC and FBXW7 mRNA expression was associated with the presence of lymph node metastasis and tumor stage III-IV. Additionally, MYC immunostaining was more frequently observed in intestinal-type than diffuse-type gastric cancers and was associated with MYC mRNA expression. In vitro studies showed that increased MYC and reduced FBXW7 expression is associated with a more invasive phenotype in gastric cancer cell lines. This result encouraged us to investigate the activity of the gelatinases MMP-2 and MMP-9 in both cell lines. Both gelatinases are synthesized predominantly by stromal cells rather than cancer cells, and it has been proposed that both contribute to cancer progression. We observed a significant increase in MMP-9 activity in ACP02 compared with ACP03 cells. These results confirmed that ACP02 cells have greater invasion capability than ACP03 cells.\ud \ud \ud \ud Conclusion\ud In conclusion, FBXW7 and MYC mRNA may play a role in aggressive biologic behavior of gastric cancer cells and may be a useful indicator of poor prognosis. Furthermore, MYC is a candidate target for new therapies against gastric cancer.This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) as grants and fellowship awards. RRB, MACS, RM, ASK and AKRS have research grants from CNPq. DQC, MFL and CRTS has a fellowship granted by CNPq and Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP)

Differential Proteomic Analysis of Noncardia Gastric Cancer from Individuals of Northern Brazil

Gastric cancer is the second leading cause of cancer-related death worldwide. The identification of new cancer biomarkers is necessary to reduce the mortality rates through the development of new screening assays and early diagnosis, as well as new target therapies. In this study, we performed a proteomic analysis of noncardia gastric neoplasias of individuals from Northern Brazil. The proteins were analyzed by two-dimensional electrophoresis and mass spectrometry. For the identification of differentially expressed proteins, we used statistical tests with bootstrapping resampling to control the type I error in the multiple comparison analyses. We identified 111 proteins involved in gastric carcinogenesis. The computational analysis revealed several proteins involved in the energy production processes and reinforced the Warburg effect in gastric cancer. ENO1 and HSPB1 expression were further evaluated. ENO1 was selected due to its role in aerobic glycolysis that may contribute to the Warburg effect. Although we observed two up-regulated spots of ENO1 in the proteomic analysis, the mean expression of ENO1 was reduced in gastric tumors by western blot. However, mean ENO1 expression seems to increase in more invasive tumors. This lack of correlation between proteomic and western blot analyses may be due to the presence of other ENO1 spots that present a slightly reduced expression, but with a high impact in the mean protein expression. In neoplasias, HSPB1 is induced by cellular stress to protect cells against apoptosis. In the present study, HSPB1 presented an elevated protein and mRNA expression in a subset of gastric cancer samples. However, no association was observed between HSPB1 expression and clinicopathological characteristics. Here, we identified several possible biomarkers of gastric cancer in individuals from Northern Brazil. These biomarkers may be useful for the assessment of prognosis and stratification for therapy if validated in larger clinical study sets.Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP

MYC, FBXW7 and TP53 copy number variation and expression in gastric cancer

BACKGROUND: \ud MYC deregulation is a common event in gastric carcinogenesis, usually as a consequence of gene amplification, chromosomal translocations, or posttranslational mechanisms. FBXW7 is a p53-controlled tumor-suppressor that plays a role in the regulation of cell cycle exit and reentry via MYC degradation.\ud METHODS: \ud We evaluated MYC, FBXW7, and TP53 copy number, mRNA levels, and protein expression in gastric cancer and paired non-neoplastic specimens from 33 patients and also in gastric adenocarcinoma cell lines. We also determined the invasion potential of the gastric cancer cell lines.\ud RESULTS: \ud MYC amplification was observed in 51.5% of gastric tumor samples. Deletion of one copy of FBXW7 and TP53 was observed in 45.5% and 21.2% of gastric tumors, respectively. MYC mRNA expression was significantly higher in tumors than in non-neoplastic samples. FBXW7 and TP53 mRNA expression was markedly lower in tumors than in paired non-neoplastic specimens. Moreover, deregulated MYC and FBXW7 mRNA expression was associated with the presence of lymph node metastasis and tumor stage III-IV. Additionally, MYC immunostaining was more frequently observed in intestinal-type than diffuse-type gastric cancers and was associated with MYC mRNA expression. In vitro studies showed that increased MYC and reduced FBXW7 expression is associated with a more invasive phenotype in gastric cancer cell lines. This result encouraged us to investigate the activity of the gelatinases MMP-2 and MMP-9 in both cell lines. Both gelatinases are synthesized predominantly by stromal cells rather than cancer cells, and it has been proposed that both contribute to cancer progression. We observed a significant increase in MMP-9 activity in ACP02 compared with ACP03 cells. These results confirmed that ACP02 cells have greater invasion capability than ACP03 cells.\ud CONCLUSION: \ud In conclusion, FBXW7 and MYC mRNA may play a role in aggressive biologic behavior of gastric cancer cells and may be a useful indicator of poor prognosis. Furthermore, MYC is a candidate target for new therapies against gastric cancer.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP