Publications by authors named "Samia Demachki"

71 Publications

Acquired acoria and iris pearls in leprosy: Case report.

Eur J Ophthalmol 2021 Jun 18:11206721211024057. Epub 2021 Jun 18.

Departamento de Oftalmologia, Hospital Universitário Bettina Ferro de Souza, Universidade Federal do Pará, Belém, Pará, Brazil.

Purpose: To describe a case of a patient presenting with acquired acoria and iris pearls, a rare eye manifestation and pathognomonic finding for leprosy; to reinforce clinical, histopathological, and therapeutic aspects of ocular involvement in leprosy.

Methods: Case report.

Case Description: A 62-year-old male presenting with acquired acoria and iris pearls in both eyes due to leprosy also had anterior uveitis and cataract. Histopathological diagnosis of iris pearls was confirmed by the presence of Hansen's bacilli. Ophthalmological examination revealed improvement of the visual acuity after iridectomy and extracapsular cataract extraction.

Conclusions: To our knowledge, this is the first reported case of acquired acoria in a leprosy patient. It led to impaired vision and reversible blindness. Proper diagnosis and ophthalmological treatment of patients with these conditions are essential for the maintenance of a good quality of life.
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http://dx.doi.org/10.1177/11206721211024057DOI Listing
June 2021

Gastric Cancer Microbiome.

Pathobiology 2021 15;88(2):156-169. Epub 2021 Feb 15.

Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Brazil,

Identifying a microbiome pattern in gastric cancer (GC) is hugely debatable due to the variation resulting from the diversity of the studied populations, clinical scenarios, and metagenomic approach. H. pylori remains the main microorganism impacting gastric carcinogenesis and seems necessary for the initial steps of the process. Nevertheless, an additional non-H. pylori microbiome pattern is also described, mainly at the final steps of the carcinogenesis. Unfortunately, most of the presented results are not reproducible, and there are no consensual candidates to share the H. pylori protagonists. Limitations to reach a consistent interpretation of metagenomic data include contamination along every step of the process, which might cause relevant misinterpretations. In addition, the functional consequences of an altered microbiome might be addressed. Aiming to minimize methodological bias and limitations due to small sample size and the lack of standardization of bioinformatics assessment and interpretation, we carried out a comprehensive analysis of the publicly available metagenomic data from various conditions relevant to gastric carcinogenesis. Mainly, instead of just analyzing the results of each available publication, a new approach was launched, allowing the comprehensive analysis of the total sample amount, aiming to produce a reliable interpretation due to using a significant number of samples, from different origins, in a standard protocol. Among the main results, Helicobacter and Prevotella figured in the "top 6" genera of every group. Helicobacter was the first one in chronic gastritis (CG), gastric cancer (GC), and adjacent (ADJ) groups, while Prevotella was the leader among healthy control (HC) samples. Groups of bacteria are differently abundant in each clinical situation, and bacterial metabolic pathways also diverge along the carcinogenesis cascade. This information may support future microbiome interventions aiming to face the carcinogenesis process and/or reduce GC risk.
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http://dx.doi.org/10.1159/000512833DOI Listing
February 2021

Differential regulation of in gastric cancer by DNA methylation.

Epigenetics 2021 Feb 8:1-7. Epub 2021 Feb 8.

Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, Brazil.

Gastric cancer (GC) is one of the leading types of fatal cancer worldwide. Epigenetic manipulation of cancer cells is a useful tool to better understand gene expression regulatory mechanisms and contributes to the discovery of novel biomarkers. Our research group recently reported a list of 83 genes that are potentially modulated by DNA methylation in GC cell lines. Herein, we further explored the regulation of one of these genes, , in clinical samples. expression was evaluated by RT-qPCR, and DNA methylation was studied using next-generation bisulphite sequencing in 36 GC and paired adjacent nonneoplastic tissue samples. We showed that both reduced mRNA levels and increased exon methylation were associated with undifferentiated and poorly differentiated tumours. Moreover, gene expression and methylation levels were inversely correlated at the +45 exon CpG site. We suggest that DNA hypermethylation may contribute to reducing expression in undifferentiated and poorly differentiated GC. Therefore, our results show how some genes may be useful to stratify patients who are more likely to benefit from epigenetic therapy. AR: androgen receptor; 5-AZAdC: 5-aza-2'-deoxycytidine; : beta-2-microglobulin; : glyceraldehyde-3-phosphate dehydrogenase; GC: gastric cancer; GLM: general linear model; : leucine-rich repeat containing 37 member A2; SD: standard deviation; TFII-I: general transcription factor II-I; TSS: transcription start site; XBP1: X-box binding protein 1.
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http://dx.doi.org/10.1080/15592294.2021.1878724DOI Listing
February 2021

Sex and FOXP3 gene rs2232365 polymorphism may be associated with the clinical and pathological aspects of chronic viral diseases.

BMC Immunol 2020 11 19;21(1):60. Epub 2020 Nov 19.

Virology Laboratory, Biological Sciences Institute, Federal University of Pará (Universidade Federal do Pará - UFPA), Belém, Brazil.

Background: The forkhead box protein 3 (FOXP3) transcription factor is one of the main markers of immunological suppression in different pathological profiles, and the presence of polymorphic variants may alter the gene expression of this factor. Despite descriptions of an association between the presence of the rs2232365 polymorphism and chronic diseases, the role of the sex variant in this context has not yet been elucidated, as the FOXP3 gene is located on the human sex chromosome X.

Results: To contribute to this topic, 323 women and 373 men were enrolled in the study, of which 101 were diagnosed with chronic viral liver diseases (39 women and 62 men), 67 with HTLV-1 infection (44 women and 23 men), 230 with coronary artery disease (91 women and 139 men) and 298 healthy and uninfected blood donors (149 women and men). They were genotyped for the rs2232365 polymorphism. The rs2232365 polymorphism was associated with clinical and pathological aspects and biomarkers of viral infections only in men, with functional differences between different infections.

Conclusions: A relationship is suggested between sex and FOXP3 rs2232365 polymorphism, resulting in different biological repercussions.
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http://dx.doi.org/10.1186/s12865-020-00387-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678194PMC
November 2020

Global Analyses of Expressed Piwi-Interacting RNAs in Gastric Cancer.

Int J Mol Sci 2020 Oct 16;21(20). Epub 2020 Oct 16.

Graduate Program in Genetics and Molecular Biology, Laboratory of Human and Medical Genetics, Federal University of Pará, Belém, Pará 66075-110, Brazil.

Gastric cancer (GC) represents a notable amount of morbidity and mortality worldwide. Understanding the molecular basis of CG will offer insight into its pathogenesis in an attempt to identify new molecular biomarkers to early diagnose this disease. Therefore, studies involving small non-coding RNAs have been widely explored. Among these, PIWI-interacting RNAs (piRNAs) are an emergent class that can play important roles in carcinogenesis. In this study, small-RNA sequencing was used to identify the global piRNAs expression profile (piRNome) of gastric cancer patients. We found 698 piRNAs in gastric tissues, 14 of which were differentially expressed (DE) between gastric cancer (GC), adjacent to gastric cancer (ADJ), and non-cancer tissues (NC). Moreover, three of these DE piRNAs (piR-48966*, piR-49145, piR-31335*) were differently expressed in both GC and ADJ samples in comparison to NC samples, indicating that the tumor-adjacent tissue was molecularly altered and should not be considered as a normal control. These three piRNAs are potential risk biomarkers for GC, especially piR-48966* and piR-31335*. Furthermore, an in-silico search for mRNAs targeted by the differentially expressed piRNAs revealed that these piRNAs may regulate genes that participate in cancer-related pathways, suggesting that these small non-coding RNAs may be directly and indirectly involved in gastric carcinogenesis.
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http://dx.doi.org/10.3390/ijms21207656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593925PMC
October 2020

Lymph nodes may be a source for immunetherapy in gastric cancer.

Oncotarget 2020 May 12;11(19):1729-1736. Epub 2020 May 12.

Núcleo de Pesquisas em Oncologia, Hospital Universitário João de Barros Barreto, Belém-PA, Brasil.

Background: adoptive immunotherapy is a promising cancer therapy. Immune cells are capable of recognizing and destroying cancer cells and represent a powerful strategy, however, this approach remains technically complicated, due to the need to select and isolate immune cells from these, present cancer antigens to those cells, expanding and reinjecting them. Lymph nodes recovered during gastric cancer surgery may represent an option for immunotherapy, since they harbor an enormous amount of immune cells, which have already been presented to cancer antigens. The advantage of selecting only cancer-negative lymph has not been determined yet. The status of immune checkpoints in the immune cells within the lymph nodes was analyzed in order to try to solve this problem.

Materials And Methods: Tissue microarrays were constructed and automated immunostaining for PD-1 and PD-L1 was performed on 143 lymph nodes from 70 patients with gastric adenocarcinoma.

Results: In positive nodes, PD-L1 was only positivity in cancer cells (6%) and PD-1 was positive for B lymphocytes (60%), T lymphocytes (70%) and one case in cancer cells (2.5%). In negative nodes, most cases were positive for PD-1 in B (73.1%) and T (71.65%) lymphocytes.

Conclusions: Expression of PD-1 and PD-L1 in gastric cancer lymph nodes was demonstrated for the first time. PD-1 is expressed in positive and negative nodes, which could activate the PD-1 pathway. Lymphocytes from tumor-free lymph nodes were negative for PD-L1, and this might represent an advantage for selecting these lymph nodes as a potential source of immune cells for adoptive immunotherapy.
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http://dx.doi.org/10.18632/oncotarget.27578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233812PMC
May 2020

Hepatic metastasis in Frantz's tumor: A case report.

Int J Surg Case Rep 2020 11;71:66-69. Epub 2020 May 11.

Research Center on Oncology, Institute of Health Sciences, Federal University of Pará, Mundurucus Street, N.4487, Guamá, Belém - PA, 66073-000, Belém, PA, Brazil. Electronic address:

Introduction: Frantz's Tumor or Solid Pseudopapillary Neoplasm (SPN) is rare with a solid-cystic pattern, and most common in young women.

Presentation Of Case: This study based on guidelines for case reports (SCARE) reports a case of SPN in a teenager aged 13 years at the diagnosis time, attended at a teaching public hospital in Brazil, which evolved into liver metastases. Clinical, laboratory, therapeutic and imaging data were collected from the physical chart and analyzed in light of current publications on the topic. The first consultation occurred in January 2012, where weight loss, fever, vomiting, left-sided hypochondrium and epigastric pain were reported. Imaging exams evidenced an expansive heterogeneous process in the pancreatic tail; however, laboratory exams and tumor markers did not present alteration in relation to reference values. In March of 2012, she underwent caudal body pancreatectomy, splenectomy, segmental colectomy and colo-coloanastomosis as a function of the intraoperative findings. After 63 months, right-sided hepatectomy was performed to resect metastases. Currently, she is undergoing outpatient monitoring, without complaint or alterations in imaging and laboratory exams, totaling 100 months of global survival.

Discussion: This is an interesting case report of a rare tumor, in so far as without any adjuvant chemotherapies, an 8-year long survival time could be achieved in this particular type of tumor despite initially large tumor expansion and later liver metastases.

Conclusion: Additional epidemiological studies, molecular and clinical trials are required to increase knowledge on SPN.
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http://dx.doi.org/10.1016/j.ijscr.2020.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260607PMC
May 2020

The impact of DNA demethylation on the upregulation of the NRN1 and TNFAIP3 genes associated with advanced gastric cancer.

J Mol Med (Berl) 2020 05 13;98(5):707-717. Epub 2020 Apr 13.

Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, São Paulo, 04023900, Brazil.

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Very few therapeutic options are currently available in this neoplasia. The use of 5-Aza-2'-deoxycytidine (5-AZAdC) was approved for the treatment of myelodysplastic syndromes, and this drug can treat solid tumours at low doses. Epigenetic manipulation of GC cell lines is a useful tool to better understand gene expression regulatory mechanisms for clinical applications. Therefore, we compared the gene expression profile of 5-AZAdC-treated and untreated GC cell lines by a microarray assay. Among the genes identified in this analysis, we selected NRN1 and TNFAIP3 to be evaluated for gene expression by RT-qPCR and DNA methylation by bisulfite DNA next-generation sequencing in 43 and 52 pairs of GC and adjacent non-neoplastic tissue samples, respectively. We identified 83 candidate genes modulated by DNA methylation in GC cell lines. Increased expression of NRN1 and TNFAIP3 was associated with advanced tumours (P < 0.05). We showed that increased NRN1 and TNFAIP3 expression seems to be regulated by DNA demethylation in GC samples: inverse correlations between the mRNA and DNA methylation levels in the promoter of NRN1 (P < 0.05) and the intron of TNFAIP3 (P < 0.05) were detected. Reduced NRN1 promoter methylation was associated with III/IV TNM stage tumours (P = 0.03) and the presence of Helicobacter pylori infection (P = 0.02). The identification of demethylated activated genes in GC may be useful in clinical practice, stratifying patients who are less likely to benefit from 5-AZAdC-based therapies. KEY MESSAGES: Higher expression of NRN1 and TNFAIP3 is associated with advanced gastric cancer (GC). NRN1 promoter hypomethylation contributes to gene upregulation in advanced GC. TNFAIP3 intronic-specific CpG site demethylation contributes to gene upregulation in GC. These findings may be useful to stratify GC patients who are less likely to benefit from DNA demethylating-based therapies.
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http://dx.doi.org/10.1007/s00109-020-01902-1DOI Listing
May 2020

NGF (-198C > T, Ala35Val) and p75 (Ser205Leu) gene mutations are associated with liver function in different histopathological profiles of the patients with chronic viral hepatitis in the Brazilian Amazon.

Mol Med 2020 01 29;26(1):12. Epub 2020 Jan 29.

Virology Laboratory, Biological Science Institute, Federal University of Pará, Belém, Pará, Brazil.

Backgrounds: Neural growth factor (NGF) is a neurotrophin that can interact with the p75 receptor and initiate a cascade of reactions that determines cell survival or death, and both are associated with the physiology of liver tissue. Single nucleotide polymorphisms (SNPs) in the NGF and p75 genes have been investigated in different pathologies; however, there are no studies that have analyzed their biological roles in the hepatic microenvironment. In the present study, we evaluated the impact of SNPs in these genes on the maintenance of liver function at different stages of inflammation and fibrosis in patients with chronic viral liver disease in the Brazilian Amazon.

Methods: The SNPs -198C > T, Arg80Gln, Val72Met, Ala35Val, Ala18Ala and Ser205Leu were genotyped by real-time PCR in samples from patients with chronic viral hepatitis stratified by stage of inflammation and liver fibrosis. Histopathological, viral load (VL), liver enzyme and comorbidities data were obtained from updated medical records. Other aspects were highlighted by applied epidemiological questionnaires.

Results: The -198C/T and Ala35Val polymorphisms in NGF were associated with changes in histopathological profiles, VL and liver enzymes. Ser205Leu polymorphism in p75 was associated only with changes in VL and liver enzymes. Polymorphic frequencies were variable among different ethnic populations, mainly for biologically relevant polymorphisms. A multifactorial network of interactions has been established based on genetic, virological, behavioral and biochemical aspects.

Conclusion: Mutations in the NGF (-198C > T, Ala35Val) and p75 (Ser205Leu) genes, within the list of multifactorial aspects, are associated with liver function in different histopathological profiles of patients with chronic viral liver disease in the Brazilian Amazon.
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http://dx.doi.org/10.1186/s10020-019-0134-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990582PMC
January 2020

Hepatic TLR4, MBL and CRP gene expression levels are associated with chronic hepatitis C.

Infect Genet Evol 2020 06 18;80:104200. Epub 2020 Jan 18.

Virology Laboratory, Biological Science Institute, Federal University of Pará, Guamá, 66075-110 Belém, Pará, Brazil. Electronic address:

Contact with HCV triggers the activation of innate mechanisms responsible for initial infection control. Host cells expressed extra- or intracellularly molecules that promote recognition of pathogen-associated molecular patterns (PAMPs). Toll-like receptor 4 (TLR4), mannose-binding lectin (MBL) and C-reactive protein (CRP) are molecules available for HCV PAMP recognition. The present study evaluated TLR4, MBL and CRP gene expression in the hepatic tissue of chronic HCV carriers (n = 22) and the association of that expression with the pathogenesis of HCV as well as the progression of liver fibrosis. Liver biopsy specimens from the HCV group were divided according to the METAVIR classification: without fibrosis and/or mild fibrosis (F0-F1), moderate fibrosis (F2), and severe fibrosis and/or cirrhosis (F3-F4) and A0-A1 (absent or mild inflammation) and A2 (moderate inflammation); normal liver samples were used as a control (n = 8). The mRNA levels of the genes studied were quantified by real-time PCR, and plasma CRP and liver enzymes were measured using an automated system. CRP and MBL expression was significantly lower in the HCV group compared to that in the control group (p < .0001 and p = .0242, respectively). TLR4 expression was higher in the HCV group than in the control group (p = .0448) and was also significantly higher (p = .0314) with lower levels of necroinflammatory activity (A0-A1), with a significant correlation between the expression of MBL with TLR4 as well as a positive correlation between plasma levels and CRP expression in the HCV group (p = .0431). Hepatic TLR4, MBL and CRP expression showed no significant association with liver enzymes nor plasma viral load. Mechanisms of HCV escape seem to influence hepatic TLR4, MBL and CRP expression, resulting in a change in the transcription profile of these proteins of innate immunity, which may contribute to virus persistence, liver fibrogenesis and loss of normal liver function.
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http://dx.doi.org/10.1016/j.meegid.2020.104200DOI Listing
June 2020

Whole mitochondrial genome sequencing highlights mitochondrial impact in gastric cancer.

Sci Rep 2019 10 31;9(1):15716. Epub 2019 Oct 31.

Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém, 66075-970, Brazil.

Mitochondria are organelles that perform major roles in cellular operation. Thus, alterations in mitochondrial genome (mtGenome) may lead to mitochondrial dysfunction and cellular deregulation, influencing carcinogenesis. Gastric cancer (GC) is one of the most incident and mortal types of cancer in Brazil, particularly in the Amazon region. Here, we sequenced and compared the whole mtGenome extracted from FFPE tissue samples of GC patients (tumor and internal control - IC) and cancer-free individuals (external control - EC) from this region. We found 3-fold more variants and up to 9-fold more heteroplasmic regions in tumor when compared to paired IC samples. Moreover, tumor presented more heteroplasmic variants when compared to EC, while IC and EC showed no significant difference when compared to each other. Tumor also presented substantially more variants in the following regions: MT-RNR1, MT-ND5, MT-ND4, MT-ND2, MT-DLOOP1 and MT-CO1. In addition, our haplogroup results indicate an association of Native American ancestry (particularly haplogroup C) to gastric cancer development. To the best of our knowledge, this is the first study to sequence the whole mtGenome from FFPE samples and to apply mtGenome analysis in association to GC in Brazil.
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http://dx.doi.org/10.1038/s41598-019-51951-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823544PMC
October 2019

Disparities in Epidemiological Profile of Gastric Adenocarcinoma in Selected Cities of Brazil

Asian Pac J Cancer Prev 2019 08 1;20(8):2253-2258. Epub 2019 Aug 1.

Medical Genomics Laboratory, International Research Center, A.C.Camargo Cancer Center, Sao Paulo, Brazil.

Background: Despite decreasing global incidence trends, gastric cancer is still among the five most incident cancers in the world and the third cancer-related cause of death. In Brazil, differences in incidence and mortality exist depending on the geographic region studied. Objective: To describe the incidence, mortality, trends and age-period-cohort of gastric cancer in three cities of Brazil (Sao Paulo, Belem and Fortaleza), in the period 1990-2012. Mortality for gastric cancer in Brazil overall and by region was described. Methods: 33,462 incident cases of gastric cancer were identified from the population-based cancer registries and 23,424 deaths from mortality information system in residents of the three cities and in Brazil were included in the study. Data for incident cases were extracted from the Population Based Cancer Registries from the National Cancer Institute (INCA). Mortality data on gastric cancer were extracted from Information Technology Department of Brazilian Public Health Care System/Health Ministry (DATASUS/MS). Mortality and incidence age standardized rates were calculated. For trends analysis the Joinpoint Regression and age-period-cohort model were applied. Results: Belem presented the highest incidence rates for gastric adenocarcinoma. Decreasing incidence trends were identified in Sao Paulo (-7.8% in men; -6.3% in women) and in Fortaleza (-1.2% in men). Increasing incidence trends were observed for women in Belem (1.8%) and Fortaleza (1.1%). In Belem (Amazon area), there was an increased risk for gastric cancer in women born after the 1960s. Overall in Brazil mortality for gastric cancer is decreasing. Mortality trends showed significant reduction, for both sexes, in the three Brazilian cities. Conclusion: Incidence of gastric cancer is increasing in women born in the sixties in Belem (Amazon region) and Fortaleza (Northeast region). In Brazil there was increase in mortality in Northeast region and decrease in others regions. More update data on incidence for Amazon and Northeast region is needed.
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http://dx.doi.org/10.31557/APJCP.2019.20.8.2253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852822PMC
August 2019

miRNome Reveals New Insights Into the Molecular Biology of Field Cancerization in Gastric Cancer.

Front Genet 2019 19;10:592. Epub 2019 Jun 19.

Laboratory of Human and Medical Genetics, Institute of Biological Sciences, Graduate Program of Genetics and Molecular Biology, Federal University of Pará, Belém, Brazil.

Background: MicroRNAs (miRNAs) play an important role in gastric carcinogenesis and have been associated with gastric field cancerization; however, their role is not fully understood in this process. We performed the miRNome sequencing of non-cancerous, adjacent to tumor and gastric cancer samples to understand the involvement of these small RNAs in gastric field cancerization.

Methods: We analyzed samples of patients without cancer as control (non-cancerous gastric samples) and adjacent to cancer and gastric cancer paired samples, and considered miRNAs with |log()| > 2 and < 0.05 to be statistically significant. The identification of target genes, functional analysis and enrichment in KEGG pathways were realized in the TargetCompare, miRTargetLink, and DAVID tools. We also performed receiver operating characteristic (ROC) curves and miRNAs that had an AUC > 0.85 were considered to be potential biomarkers.

Results: We found 14 miRNAs exclusively deregulated in gastric cancer, of which six have potential diagnostic value for advanced disease. Nine miRNAs with known tumor suppressor activities (TS-miRs) were deregulated exclusively in adjacent tissue. Of these, five have potential diagnostic value for the early stages of gastric cancer. Functional analysis of these TS-miRs revealed that they regulate important cellular signaling pathways (PI3K-Akt, HIF-1, Ras, Rap1, ErbB, and MAPK signaling pathways), that are involved in gastric carcinogenesis. Seven miRNAs were differentially expressed in both gastric cancer and adjacent regarding to non-cancerous tissues; among them, and have potential diagnostic value for early and advanced stages of the disease. Only was differentially expressed between adjacent to cancer and gastric cancer tissues. In addition, the other miRNAs identified in this study were not differentially expressed between adjacent to cancer and gastric cancer, suggesting that these tissues are very similar and that share these molecular changes.

Conclusion: Our results show that gastric cancer and adjacent tissues have a similar miRNA expression profile, indicating that studied miRNAs are intimately associated with field cancerization in gastric cancer. The overexpression of TS-miRs in adjacent tissues may be a barrier against tumorigenesis within these pre-cancerous conditions prior to the eventual formation or relapse of a tumor. Additionally, these miRNAs have a great accuracy in discriminating non-cancerous from adjacent to tumor and cancer tissues and can be potentially useful as biomarkers for gastric cancer.
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http://dx.doi.org/10.3389/fgene.2019.00592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593062PMC
June 2019

The Small Bowel Cancer Incidence Enigma.

Pathol Oncol Res 2020 Apr 5;26(2):635-639. Epub 2019 Jun 5.

Laboratório de Biologia Molecular, Hospital Ophir Loyola, Belém, 66060-281, Brazil.

Although the small bowel is a vast organ with a highly proliferative epithelium, the incidence of small bowel cancers is surprisingly low. Many factors could be involved in this unexpected cancer incidence, including difficult access to the exploration of the small bowel mucosa, which might lead to missed diagnoses of non-obstructive and non-bleeding small tumours. Moreover, possible factors that influence the low incidence include more efficient machinery of DNA replication and DNA repair enzymes, peculiarities in microbiota components, competence of the immune system, and the speed of intestinal transit. Importantly, the answer for the enigmatic risk of driver mutations caused by replication errors may be hidden in the small bowel, which is an obscure part of digestive tract that is usually inaccessible by endoscopic or colonoscopic conventional investigations. These observations warrant the necessity of an urgent exploration of small bowel features, including the evaluation of DNA replication controls and expression of DNA repair genes, in order to shed light on these obscure events.
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http://dx.doi.org/10.1007/s12253-019-00682-5DOI Listing
April 2020

Analysis of 8q24.21 miRNA cluster expression and copy number variation in gastric cancer.

Future Med Chem 2019 05 29;11(9):947-958. Epub 2019 May 29.

Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, 04023-900, Brazil.

 To analyze gene expression and copy number of five miRNAs (, , , and ) localized in this chromosome region in gastric cancer (GC).  65 paired neoplastic and non-neoplastic specimens collected from GC patients and 20 non-neoplastic gastric tissues from cancer-free individuals were included in this study. The expression levels of the five miRNAs were accessed by real time qPCR and were correlated.  , , and were upregulated in approximately 50% of GC tumors in relation to those of adjacent non-neoplastic tissues. expression was associated with gain of gene copies and was upregulated in adjacent non-neoplastic samples relative to external controls. The coexpression of the 8q24 miRNAs indicated the role of in the initiation of gastric cancer development.
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http://dx.doi.org/10.4155/fmc-2018-0477DOI Listing
May 2019

Epigenetic Field Cancerization in Gastric Cancer: microRNAs as Promising Biomarkers.

J Cancer 2019 26;10(6):1560-1569. Epub 2019 Feb 26.

Laboratory of Human and Medical Genetics, Institute of Biological Sciences, Federal University of Pará, Augusto Corrêa Avenue, 66075-110, Belém, Pará, Brazil.

The biological role of microRNAs (miRNAs) in field cancerization is unknown. To investigate the involvement of miRNAs in gastric field cancerization, we evaluated the expression profile of ten miRNAs and their diagnostic value. We used three groups of FFPE gastric samples: non-cancer (NC), cancer adjacent (ADJ) and gastric cancer (GC). The expression profiles of , , , , , , and were investigated using qRT-PCR. The results obtained by qRT-PCR were validated in Small RNA-Seq data from the TCGA database. The search for target genes of the studied miRNAs was performed in the miRTarBase public database and miRTargetLink tool, using experimentally validated interactions. In addition, we also performed the functional analysis of these genes using enrichment in KEGG pathways. The potential as biomarker was evaluated using a receiver operating characteristic (ROC) curve and the derived area under the curve (AUC>0.85) analysis. The miRNAs , , , , , , , and were up-regulated in ADJ and GC compared to NC (<0.03); and and were up-regulated in GC compared to ADJ (<0.01). , , , and were not differentially expressed between GC and ADJ, suggesting that both share similar changes (>0.1). The TS-miR was up-regulated in ADJ compared to NC and GC (<0.01); we did not observe a significant difference in the expression of this miRNA between NC and GC. This feature may be an antitumor mechanism used by cancer-adjacent tissue because this miRNA regulates the , and oncogenes. The expression level of was associated with infection status (<0.05) Functional analysis using the genes regulated by the studied miRNAs showed that they are involved in biological pathways and cellular processes that are critical for the establishment of infection and for the onset, development and progression of GC. , , , , , , and were able to discriminate NC from other tissues with great accuracy (AUC>0.85). The studied miRNAs are closely related to field cancerization, regulate genes important for gastric carcinogenesis and can be potentially useful as biomarkers in GC.
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http://dx.doi.org/10.7150/jca.27457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485221PMC
February 2019

Traps and trumps from adjacent-to-tumor samples in gastric cancer research.

Chin J Cancer Res 2018 Oct;30(5):564-567

Laboratory of Molecular Biology, Ophir Loyola Hospital, Belém 66060-281, Brazil.

The search for cancer biomarkers is frequently based on comparisons between tumors and adjacent-to-tumor samples. However, even after histological confirmation of been free of cancer cells, these adjacent-to-tumor samples might harbor molecular alterations which are not sufficient to cause them to look like cancer, but can differentiate these cells from normal cells. When comparing them, potential biomarkers are missed, and mainly the opportunity of finding initial aberrations presents in both tumors and adjacent samples, but not in true normal samples from non-cancer patients, resulting in misinterpretations about the carcinogenic process. Nevertheless, collecting adjacent-to-tumor samples brings trumps to be explored. The addition of samples from non-cancer patients opens an opportunity to increase the finds of the molecular cascade of events in the carcinogenic process. Differences between normal samples and adjacent samples might represent the first steps of the carcinogenic process. Adding samples of non-cancer patients to the analysis of molecular alterations relevant to the carcinogenic process opens a new window of opportunities to the discovery of cancer biomarkers and molecular targets.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2018.05.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232362PMC
October 2018

The -> and -> in the Gene Are Associated With Viral Load and Liver Enzyme Levels in Patients With Chronic Viral Liver Diseases.

Front Immunol 2018 4;9:2014. Epub 2018 Sep 4.

Laboratório de Virologia, Instituto de Ciências Biológicas Universidade Federal do Pará, Belém, Brazil.

The transcription factor FOXP3 is an essential marker of the development and activation of regulatory T cells (Tregs), which are cells specialized in the regulation and normal tolerance of the immune response. In the context of chronic viral liver diseases, Tregs participate in the maintenance of infections by promoting histopathological control and favor the immune escape of viral agents by suppressing the antiviral response. Single nucleotide polymorphisms (SNPs) may influence the function of FOXP3 in a number of pathological conditions. The present study sought to evaluate the influence of SNPs in the gene promoter region in patients with chronic viral liver diseases. Three SNPs (->, ->, and ->) were analyzed in groups of patients with chronic hepatitis C (CHC), active chronic hepatitis B (CHB-A), inactive chronic hepatitis B (CHB-I), and a healthy control group (CG) using real-time PCR. The frequencies of the polymorphic variants were compared between groups and correlated with liver histopathological characteristics and enzyme levels [i.e., alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT)] obtained via biopsy and from the clinical records of the participating patients, respectively. For the -> SNP, no significant differences were found in the frequencies of variants between groups or in the histological findings. Significant associations between the polymorphisms and the CHB-I group were not established. The -> SNP was associated with altered viral loads (log) and GGT levels in CHC patients with advanced stages of inflammatory activity and liver fibrosis. The -> SNP was associated with altered viral loads (log) and liver enzyme levels among CHB-A patients with milder inflammation and fibrosis. However, the frequencies of the -> and -> polymorphisms were not directly associated with the histopathological profiles of the analyzed patients. These polymorphic variants may influence hepatic function in patients with chronic viral liver diseases but are not directly associated with the establishment of the degree of inflammatory activity and liver fibrosis.
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http://dx.doi.org/10.3389/fimmu.2018.02014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131495PMC
September 2019

A common molecular signature of intestinal-type gastric carcinoma indicates processes related to gastric carcinogenesis.

Oncotarget 2018 Jan 27;9(7):7359-7371. Epub 2017 Dec 27.

Laboratório de Célula tronco, Centro de Transplante de Medula Óssea (CEMO), Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil.

Gastric carcinoma (GC) is one of the most aggressive cancers and the second leading cause of cancer death in the world. According to the Lauren classification, this adenocarcinoma is divided into two subtypes, intestinal and diffuse, which differ in their clinical, epidemiological and molecular features. Several studies have attempted to delineate the molecular signature of gastric cancer to develop new and non-invasive screening tests that improve diagnosis and lead to new treatment strategies. However, a consensus signature has not yet been identified for each condition. Thus, this work aimed to analyze the gene expression profile of Brazilian intestinal-type GC tissues using microarrays and compare the results to those of non-tumor tissue samples. Moreover, we compared our intestinal-type gastric carcinoma profile with those obtained from populations worldwide to assess their similarity. The results identified a molecular signature for intestinal-type GC and revealed that 38 genes differentially expressed in Brazilian intestinal-type gastric carcinoma samples can successfully distinguish gastric tumors from non-tumor tissue in the global population. These differentially expressed genes participate in biological processes important to cell homeostasis. Furthermore, Kaplan-Meier analysis suggested that 7 of these genes could individually be able to predict overall survival in intestinal-type gastric cancer patients.
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http://dx.doi.org/10.18632/oncotarget.23670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800908PMC
January 2018

HPV positive, wild type TP53, and p16 overexpression correlate with the absence of residual tumors after chemoradiotherapy in anal squamous cell carcinoma.

BMC Gastroenterol 2018 Feb 21;18(1):30. Epub 2018 Feb 21.

Hospital Ophir Loyola, Belém, Pará, 66060-281, Brazil.

Background: Anal residual tumors are consensually identified within six months of chemoradiotherapy and represent a persistent lesion that may have prognostic value for overall survival. The aim of this study was to evaluate the association of HPV and HIV status, p16 expression level and TP53 mutations with the absence of residual tumors (local response) in Squamous Cell Carcinoma (SCC) of the anal canal after chemoradiotherapy.

Methods: We performed a study on 78 patients with SCC of the anal canal who submitted to chemoradiotherapy and were followed for a six-month period to identify the absence or presence of residual tumors. HPV DNA was identified by polymerase chain reaction and direct sequencing, HIV RNA was detected by TaqMan amplification, p16 expression was detected by western blotting, and the mutational analysis of TP53 was performed by direct sequencing; additionally, samples carrying mutations underwent fluorescent in sit hybridization. The evaluation of the tumor response to treatment was conducted six months after the conclusion of chemoradiotherapy. The following classifications were used to evaluate the outcomes: a) no response (presence of residual tumor) and b) complete response (absence of residual tumor).

Results: The significant variables associated with the absence of residual tumors were HPV positive, p16 overexpressed, wild-type TP53, female gender, and stages I and II. Only the presence of HPV was independently correlated with the clinical response; this variable increased the chances of a response within six months by 31-fold.

Conclusions: The presence of HPV in tumor cells was correlated with the absence of a residual tumor. This correlation is valuable and can direct future therapeutic approaches in the anal canal.
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http://dx.doi.org/10.1186/s12876-018-0758-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5822520PMC
February 2018

GEJ cancers: gastric or esophageal tumors? searching for the answer according to molecular identity.

Oncotarget 2017 Nov 31;8(61):104286-104294. Epub 2017 Oct 31.

Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Brazil.

The 7th edition of Union for International Cancer Control (UICC) staging system moved gastroesophageal junction (GEJ) cancers from gastric to esophageal group. Since clinical management is strongly influenced by this staging system, we looked at molecular fingerprints of GEJ tumors and compared to gastric and esophageal profiles. We aimed at elucidating whether GEJ cancers cluster with gastric or esophageal groups according to mRNA and microRNA expression pattern, since this might represent tumor identity. The clinical and expression data were downloaded from The Cancer Genome Atlas (TCGA) with 395 stomach, 184 esophagus and 521 colon samples for mRNA analyses and 392 stomach, 175 esophagus and 459 colon samples for microRNA comparisons. Both Principal Component Analysis (PCA) and Heat Map plots were performed in R platform, using Log transformation of RPKM normalized data. Differential Expression Analysis was also performed in R, using RAW data and the DESeq2 package. The mRNAs and microRNAs were tagged as differentially expressed if they met the following criteria: i) FDR adjusted p-value < 0.05; and ii) |Log (fold-change)| > 2. Esophagus squamous cell carcinoma (ESCC) clustered apart of the others tumors, while adenocarcinomas (AC) clustered all together according to both mRNAs and microRNAs expression patterns. The HMs of the differentially expressed mRNAs and microRNAs also demonstrated that ESCC belongs to a different group, while AC molecular signature of esophagus looks like AC of the cardia and non cardia regions. Even distal gastric cancers are quite similar to AC of the lower esophagus, demonstrating that esophagus AC relies much closer to gastric cancers than to esophagus cancers. By using robust molecular fingerprints, it was strongly demonstrated that GEJ tumors looks more like gastric cancers than esophageal cancers, despite of tumor heterogeneity.
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http://dx.doi.org/10.18632/oncotarget.22216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732806PMC
November 2017

The comprehensive expression analysis of circular RNAs in gastric cancer and its association with field cancerization.

Sci Rep 2017 11 6;7(1):14551. Epub 2017 Nov 6.

Laboratory of Human and Medical Genetics, Federal University of Pará, Belém, Pará, Brazil.

Circular RNAs comprise a new class of long noncoding RNAs characterized by their 5' and 3' ends covalently joined. Previous studies have demonstrated that some circular RNAs act as microRNA sponges, and are associated with cellular proliferation in cancer. We were the first to analyze the global expression of circular RNAs in samples of patients without gastric cancer, gastric cancer, and matched tumor-adjacent gastric tissue. Among the samples, we identified 736 previously annotated circular RNAs by RNA-Seq. The tumor-adjacent tissue presented the higher abundance of circular RNAs and could not be considered as a normal tissue, reinforcing the notion of field effect in gastric cancer. We identified five differentially expressed circular RNAs that may be potential biomarkers of this type of cancer. We also predicted candidate microRNAs targets of the highest expressed circular RNAs in gastric tissues and found five miRNAs. Overall, our results support the hypothesis of circular RNAs representing a novel factor in the dynamic epigenetic network of gene regulation, which involves the microRNAs, its mRNAs targets, and the circular RNAs-derived genes. Further studies are needed to elucidate the roles and the functional relevance of the circular RNAs in human diseases.
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http://dx.doi.org/10.1038/s41598-017-15061-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673933PMC
November 2017

HBV Viral Load and Liver Enzyme Levels May Be Associated with the Wild AA Genotype.

Mediators Inflamm 2017 12;2017:3718451. Epub 2017 Mar 12.

Laboratory of Virology, Institute of Biological Sciences, Universidade Federal do Pará (UFPA), Guamá, 66075-110 Belém, PA, Brazil.

The present study investigated the frequencies of rs1800450 ( B, G>A), rs1800451 ( C, G>A), and rs5030737 ( D, C>T) polymorphisms in exon 1 of the gene among patients with chronic viral hepatitis. Blood samples from patients infected with hepatitis B virus (HBV; = 65), hepatitis C virus (HCV; = 92), and a noninfected control group ( = 300) were investigated. The presence of polymorphisms was detected using a real-time polymerase chain reaction to correlate with liver disease pathogenesis and fibrosis staging according to the Metavir classification. The genotypic and allelic frequencies showed no significant differences between the groups, but patients with active HBV and the wild genotype presented a positive correlation between increased transaminase and HBV DNA levels and the presence of mild to moderate fibrosis. Patients with HCV and the wild genotype presented mild inflammation and higher HCV RNA levels, although the same association was not observed for the fibrosis scores. The results suggest that the mutations in exon 1 of the gene do not contribute directly to the clinical and laboratory features of HCV and HBV infections, but further studies should be performed to confirm whether the wild genotype has indirect effect on disease progression.
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http://dx.doi.org/10.1155/2017/3718451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5376955PMC
August 2017

MYC Amplification as a Predictive Factor of Complete Pathologic Response to Docetaxel-based Neoadjuvant Chemotherapy for Breast Cancer.

Clin Breast Cancer 2017 06 24;17(3):188-194. Epub 2016 Dec 24.

Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém, Brazil; Laboratório de Biologia Molecular, Hospital Ophir Loyola, Belém, Brazil.

Background: Neoadjuvant chemotherapy is a standard treatment for stage II and III breast cancer. The identification of biomarkers that may help in the prediction of response to neoadjuvant therapies is necessary for a more precise definition of the best drug or drug combination to induce a better response.

Material And Methods: We assessed the role of Ki67, hormone receptors expression, HER2, MYC genes and their protein status, and KRAS codon 12 mutations as predictor factors of pathologic response to anthracycline-cyclophosphamide (AC) followed by taxane docetaxel (T) neoadjuvant chemotherapy (AC+T regimen) in 51 patients with invasive ductal breast cancer.

Results: After neoadjuvant chemotherapy, 82.4% of patients showed pathologic partial response, with only 9.8% showing pathologic complete response. In multivariate analysis, MYC immunoreactivity and high MYC gain defined as MYC/nucleus ≥ 5 were significant predictor factors for pathologic partial response. Using the receiver operating characteristic curve analysis, the ratio of 2.5 MYC/CEP8 (sensitivity of 80% and specificity of 89.1%) or 7 MYC/nuclei copies (sensitivity of 80% and specificity of 73.9%) as the best cutoff in predicting a pathologic complete response was identified. Thus, MYC may have a role in chemosensitivity to AC and/or docetaxel drugs. Additionally, MYC amplification may be a predictor factor of pathologic response to the AC+T regimen in patients with breast cancer. Moreover, patients with an increased number of MYC copies showed pathologic complete response to this neoadjuvant treatment more frequently.

Conclusion: The analysis of MYC amplification may help in the identification of patients that may have a better response to AC+T treatment.
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http://dx.doi.org/10.1016/j.clbc.2016.12.005DOI Listing
June 2017

Identification of and amplification in gastric cancer by comprehensive genomic profiling of gastric cancer cell lines.

World J Gastroenterol 2016 Nov;22(43):9506-9514

Danielle Queiroz Calcagno, Sylvia Santomi Takeno, Carolina Oliveira Gigek, Mariana Ferreira Leal, Fernanda Wisnieski, Elizabeth Suchi Chen, Maria Isabel Melaragno, Marília Cardoso Smith, Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, São Paulo, SP 04021-001, Brazil.

Aim: To identify common copy number alterations on gastric cancer cell lines.

Methods: Four gastric cancer cell lines (ACP02, ACP03, AGP01 and PG100) underwent chromosomal comparative genome hybridization and array comparative genome hybridization. We also confirmed the results by fluorescence hybridization analysis using the bacterial artificial chromosome clone and quantitative real time PCR analysis.

Results: The amplification of 9p13.3 was detected in all cell lines by both methodologies. An increase in the copy number of 9p13.3 was also confirmed by fluorescence hybridization analysis. Moreover, the interleukin 11 receptor alpha () and maternal embryonic leucine zipper kinase () genes, which are present in the 9p13.3 amplicon, revealed gains of the gene in all the cell lines studied. Additionally, a gain in the copy number of and was observed in 19.1% (13/68) and 55.9% (38/68) of primary gastric adenocarcinoma samples, respectively.

Conclusion: The characterization of a small gain region at 9p13.3 in gastric cancer cell lines and primary gastric adenocarcinoma samples has revealed as a candidate target gene that is possibly related to the development of gastric cancer.
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http://dx.doi.org/10.3748/wjg.v22.i43.9506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116594PMC
November 2016

BMP8B Is a Tumor Suppressor Gene Regulated by Histone Acetylation in Gastric Cancer.

J Cell Biochem 2017 04 10;118(4):869-877. Epub 2016 Nov 10.

Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo 04023900, São Paulo, Brazil.

Different from genetic alterations, the reversible nature of epigenetic modifications provides an interesting opportunity for the development of clinically relevant therapeutics in different tumors. In this study, we aimed to screen and validate candidate genes regulated by the epigenetic marker associated with transcriptional activation, histone acetylation, in gastric cancer (GC). We first compared gene expression profile of trichostatin A-treated and control GC cell lines using microarray assay. Among the 55 differentially expressed genes identified in this analysis, we chose the up-regulated genes BMP8B and BAMBI for further analyses, that included mRNA and histone acetylation quantification in paired GC and nontumor tissue samples. BMP8B expression was reduced in GC compared to nontumor samples (P < 0.01). In addition, reduced BMP8B expression was associated with poorly differentiated GC (P = 0.02). No differences or histopathological associations were identified concerning BAMBI expression. Furthermore, acetylated H3K9 and H4K16 levels at BMP8B were increased in GC compared to nontumors (P < 0.05). However, reduced levels of acetylated H3K9 and H4K16 were associated with poorly differentiated GC (P < 0.05). Reduced levels of acetylated H3K9 was also associated with diffuse-type histological GC (P < 0.05). Notably, reduced BMP8B mRNA and acetylated H4K16 levels were positively correlated in poorly differentiated GC (P < 0.05). Our study demonstrated that BMP8B seems to be a tumor suppressor gene regulated by H4K16 acetylation in poorly differentiated GC. Therefore, BMP8B may be a potential target for TSA-based therapies in this GC sample subset. J. Cell. Biochem. 118: 869-877, 2017. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jcb.25766DOI Listing
April 2017

Intrahepatic mRNA Expression of FAS, FASL, and FOXP3 Genes Is Associated with the Pathophysiology of Chronic HCV Infection.

PLoS One 2016 31;11(5):e0156604. Epub 2016 May 31.

Laboratory of Virology, Institute of Biological Sciences, Federal University of Pará (Universidade Federal do Pará -UFPA), Belém, Pará, Brazil.

Unlabelled: This study aimed to evaluate the relative mRNA expression of Fas receptor (FAS), Fas ligand (FASL), and forkhead box protein 3 (FOXP3) in liver biopsy specimens obtained from patients with viral and non-viral chronic hepatitis and correlate their expression with the fibrosis stage. A total of 51 liver biopsy specimens obtained from HBV (n = 6), HCV (n = 28), and non-viral hepatic disease (NVHD) (n = 9) patients and from individuals with normal liver histology (n = 8) (control-CT) were analyzed. Quantifications of the target genes were assessed using qPCR, and liver biopsies according to the METAVIR classification. The mRNA expression levels of FAS and FASL were lower in the CT group compared to the groups of patients. The increase in the mRNA expression of FAS and FASL was correlated with higher levels of inflammation and disease progression, followed by a decline in tissues with cirrhosis, and it was also associated with increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Higher mRNA expression of FOXP3 was observed in the HCV and NVHD groups, with the peak observed among patients with cirrhosis. The increased FOXP3 mRNA expression was positively correlated with increased FAS and FASL mRNA expression and the AST and ALT levels in all patients.

Conclusions: These results suggest that regardless of the cause, the course of chronic liver disease may be modulated by the analyzed genes and correlated with an increase in regulatory T cells during the liver damage followed by hepatocyte destruction by Fas/FasL system and subsequent non specific lymphocytic infiltrate accumulation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0156604PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887037PMC
July 2017

hsa-miR-29c and hsa-miR-135b differential expression as potential biomarker of gastric carcinogenesis.

World J Gastroenterol 2016 Feb;22(6):2060-70

Amanda Ferreira Vidal, Aline MP Cruz, Leandro Magalhães, Adenilson L Pereira, Ana KM Anaissi, Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Pará, Cidade Universitária Prof. José Silveira Netto, Belém, PA 66075-970, Brasil.

Aim: To investigate the expression profiles of hsa-miR-29c and hsa-miR-135b in gastric mucosal samples and their values as gastric carcinogenesis biomarkers.

Methods: The expression levels of hsa-miR-29c and hsa-miR-135b in normal gastric mucosa, non-atrophic chronic gastritis, intestinal metaplasia and intestinal-type gastric adenocarcinoma were analysed using quantitative real-time PCR. The difference between hsa-miR-29c and hsa-miR-135b expression profiles in the grouped samples was evaluated by ANOVA and Student's t-test tests. The results were adjusted for multiple testing by using Bonferroni's correction. P values ≤ 0.05 were considered statistically significant. To evaluate hsa-miR-29c and hsa-miR-135b expressions as potential biomarkers of gastric carcinogenesis, we performed a receiver operating characteristic curve analysis and the derived area under the curve, and a Categorical Principal Components Analysis. In silico identification of the genetic targets of hsa-miR-29c and hsa-miR-135b was performed using different prediction tools, in order to identify possible genes involved in gastric carcinogenesis.

Results: The expression levels of hsa-miR-29c were higher in normal gastric mucosal samples, and decreased progressively in non-atrophic chronic gastritis samples, intestinal metaplasia samples and intestinal-type gastric adenocarcinoma samples. The expression of hsa-miR-29c in the gastric lesions showed that non-atrophic gastritis have an intermediate profile to gastric normal mucosa and intestinal-type gastric adenocarcinoma, and that intestinal metaplasia samples presented an expression pattern similar to that in intestinal-type gastric adenocarcinoma. This microRNA (miRNA) has a good discriminatory accuracy between normal gastric samples and (1) intestinal-type gastric adenocarcinoma; and (2) intestinal metaplasia, and regulates the DMNT3A oncogene. hsa-miR-135b is up-regulated in non-atrophic chronic gastritis and intestinal metaplasia samples and down-regulated in normal gastric mucosa and intestinal-type gastric adenocarcinoma samples. Non-atrophic chronic gastritis and intestinal metaplasia are significantly different from normal gastric mucosa samples. hsa-miR-135b expression presented a greater discriminatory accuracy between normal samples and gastric lesions. This miRNA was associated with Helicobacter pylori presence in non-atrophic chronic gastritis samples and regulates the APC and KLF4 tumour suppressor genes.

Conclusion: Our results provide evidence of epigenetic alterations in non-atrophic chronic gastritis and intestinal metaplasia and suggest that hsa-miR-29c and hsa-miR-135b are promising biomarkers of gastric carcinogenesis.
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http://dx.doi.org/10.3748/wjg.v22.i6.2060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726678PMC
February 2016

CDKN1A histone acetylation and gene expression relationship in gastric adenocarcinomas.

Clin Exp Med 2017 Feb 14;17(1):121-129. Epub 2015 Nov 14.

Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, 04023900, Brazil.

CDKN1A is a tumor suppressor gene involved in gastric carcinogenesis and is a potential target for histone deacetylase inhibitor-based therapies. Upregulation of CDKN1A is generally observed in several cell lines after histone deacetylase inhibitor treatment; however, little is known about the histone acetylation status associated with this gene in clinical samples, including gastric tumor tissue samples. Therefore, our goal was to quantify the H3K9 and H4K16 acetylation levels associated with three CDKN1A regions in 21 matched pairs of gastric adenocarcinoma and corresponding adjacent non-tumor samples by chromatin immunoprecipitation and to correlate these data with the gene expression. Our results demonstrated that the -402, -20, and +182 CDKN1A regions showed a significantly increased acetylation level in at least one of the histones evaluated (p < 0.05, for all comparisons), and these levels were positively correlated in gastric tumors. However, an inverse correlation was detected between both H3K9 and H4K16 acetylation at the -402 CDKN1A region and mRNA levels in gastric tumors (r = -0.51, p = 0.02; r = -0.60, p < 0.01, respectively). Furthermore, increased H4K16 acetylation at the -20 CDKN1A region was associated with gastric tumors of patients without lymph node metastasis (p = 0.04). These results highlight the complexity of these processes in gastric adenocarcinoma and contribute to a better understanding of CDKN1A regulation in carcinogenesis.
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http://dx.doi.org/10.1007/s10238-015-0400-3DOI Listing
February 2017
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