RESUMEN

Background: The diagnosis and treatment of lung, colon, and gastric cancer through the histologic characteristics and genomic biomarkers have not had a strong impact on the mortality rates of the top three global causes of death by cancer. Methods: Twenty-five transcriptomic analyses (10 lung cancer, 10 gastric cancer, and 5 colon cancer datasets) followed our own bioinformatic pipeline based on the utilization of specialized libraries from the R language and DAVID´s gene enrichment analyses to identify a regulatory metafirm network of transcription factors and target genes common in every type of cancer, with experimental evidence that supports its relationship with the unlocking of cell phenotypic plasticity for the acquisition of the hallmarks of cancer during the tumoral process. The network's regulatory functional and signaling pathways might depend on the constant crosstalk with the microbiome network established in the oral-gut-lung axis. Results: The global transcriptomic network analysis highlighted the impact of transcription factors (SOX4, TCF3, TEAD4, ETV4, and FOXM1) that might be related to stem cell programming and cancer progression through the regulation of the expression of genes, such as cancer-cell membrane receptors, that interact with several microorganisms, including human T-cell leukemia virus 1 (HTLV-1), the human papilloma virus (HPV), the Epstein-Barr virus (EBV), and SARS-CoV-2. These interactions can trigger the MAPK, non-canonical WNT, and IFN signaling pathways, which regulate key transcription factor overexpression during the establishment and progression of lung, colon, and gastric cancer, respectively, along with the formation of the microbiome network. Conclusion: The global transcriptomic network analysis highlights the important interaction between key transcription factors in lung, colon, and gastric cancer, which regulates the expression of cancer-cell membrane receptors for the interaction with the microbiome network during the tumorigenic process.

Asunto(s)

Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Transcriptoma , Humanos , Neoplasias Pulmonares/microbiología , Neoplasias Pulmonares/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Biología Computacional , Pulmón/microbiología , Pulmón/patología , Boca/microbiología , Transducción de Señal , Microbioma Gastrointestinal/genética , Microbiota/genética , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/genética , Regulación Neoplásica de la Expresión Génica

RESUMEN

PURPOSE: Although the intestinal subtype of gastric cancer (GC) is most prevalent around the world, a relatively high prevalence of the diffuse subtype has been reported in some populations of Central American countries, including Guatemala. This study aimed to investigate whether differences exist in the prevalence of the two GC subtypes in the two main ethnic groups in Guatemala, namely Mayan and Mestizo (known as Ladino in Guatemala), between whom significant socioeconomic disparities exist, and to determine whether there is an association with Helicobacter pylori/CagA seropositivity. MATERIALS AND METHODS: Participants included 65 patients with GC and 135 age-/sex-matched controls. Data on ethnicity, H. pylori and CagA seropositivity status, as well as tumor subtype (diffuse or intestinal) were collected. Logistic regression models were fitted to examine the relationship between predictor variables (age, sex, ethnicity, H. pylori, and CagA) and the binary response variable (tumor type). Model selection was based on the Akaike information criterion. RESULTS: The prevalence of diffuse GC was found to be significantly higher in the Mayan compared with the Mestizo population in Guatemala. Although seropositivity for CagA was significantly higher in patients with GC, there were no significant differences between the two GC subtypes. CONCLUSION: This study suggests that there are differences in the prevalence of intestinal and diffuse GC histologic subtypes between the two main ethnic groups in Guatemala. Further studies are warranted, given the potential higher prevalence of the more severe GC subtype in the most vulnerable population.

Asunto(s)

Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/patología , Neoplasias Gástricas/microbiología , Guatemala/epidemiología , Femenino , Masculino , Persona de Mediana Edad , Prevalencia , Helicobacter pylori/aislamiento & purificación , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/complicaciones , Anciano , Adulto , Antígenos Bacterianos

RESUMEN

Gastric cancer is an aggressive and multifactorial disease. Helicobacter pylori (H. pylori) is identified as a significant etiological factor in gastric cancer. Although only a fraction of patients infected with H. pylori progresses to gastric cancer, bacterial infection is critical in the pathology and development of this malignancy. The pathogenic mechanisms of this bacterium involve the disruption of the gastric epithelial barrier and the induction of chronic inflammation, oxidative stress, angiogenesis and metastasis. Adherence molecules, virulence (CagA and VacA) and colonization (urease) factors are important in its pathogenicity. On the other hand, resveratrol is a natural polyphenol with anti-inflammatory and antioxidant properties. Resveratrol also inhibits cancer cell proliferation and angiogenesis, suggesting a role as a potential therapeutic agent against cancer. This review explores resveratrol as an alternative cancer treatment, particularly against H. pylori-induced gastric cancer, due to its ability to mitigate the pathogenic effects induced by bacterial infection. Resveratrol has shown efficacy in reducing the proliferation of gastric cancer cells in vitro and in vivo. Moreover, the synergistic effects of resveratrol with chemotherapy and radiotherapy underline its therapeutic potential. However, further research is needed to fully describe its efficacy and safety in treating gastric cancer.

Asunto(s)

Infecciones por Helicobacter , Helicobacter pylori , Resveratrol , Neoplasias Gástricas , Resveratrol/farmacología , Resveratrol/uso terapéutico , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/tratamiento farmacológico , Humanos , Helicobacter pylori/efectos de los fármacos , Helicobacter pylori/patogenicidad , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/microbiología , Proliferación Celular/efectos de los fármacos , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico

RESUMEN

BACKGROUND: Helicobacter pylori (H. pylori) is a gram-negative bacterium associated with the etiology of several gastrointestinal tract pathologies, and cagA-positive (cagA+) strains are found in populations with gastric ulcers and precancerous lesions, inducing pro-inflammatory responses. The development of neoplasms is related to microRNA (miRNA) dysregulation, indicating highly expressed miRNA-629. The article aims to correlate the expression level of miRNA-629 with the presence of H. pylori and the pathogenicity marker cagA. METHODS: 203 gastric biopsy samples were evaluated from individuals with normal gastric tissue (n=60), gastritis (n=96), and gastric cancer (n=47) of both genders and over 18 years old. The samples were subdivided according to the presence or absence of H. pylori, detected by polymerase chain reaction (PCR). RNA was extracted using a commercial kit and quantified. Complementary DNA (cDNA) was synthesized using commercial kits, and the relative expression was calculated using the 2-ΔΔCt method. RESULTS: Individuals infected with H. pylori are nine times more likely to develop gastric cancer. Cancer patients appeared to have decreased expression of miRNA-629; however, the presence of the bacterium would not influence this reduction. Individuals in the cancer group showed lower miRNA-629 expression when cagA+; however, in the control group, the expression was higher when cagA+. CONCLUSION: H. pylori is a factor involved in the etiology and progression of gastric diseases. Reduction in miRNA-629 expression in cancer patients occurs independent of the presence of the bacterium, but when the cagA pathogenicity marker is present, it induces changes in the gene expression of the respective miRNA.

Asunto(s)

Antígenos Bacterianos , Proteínas Bacterianas , Infecciones por Helicobacter , Helicobacter pylori , MicroARNs , Neoplasias Gástricas , Humanos , Helicobacter pylori/genética , Helicobacter pylori/patogenicidad , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/genética , Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , MicroARNs/genética , MicroARNs/análisis , Femenino , Masculino , Infecciones por Helicobacter/microbiología , Persona de Mediana Edad , Adulto , Anciano , Gastritis/microbiología

RESUMEN

Helicobacter pylori (H. pylori) is responsible for causing chronic gastritis, which can cause peptic ulcer and premalignant lesions such as atrophic gastritis, intestinal metaplasia, and dysplasia, with the risk of developing gastric cancer. Recent data describe that H. pylori colonizes the gastric mucosa of more than 50% of the world's population; however, this bacterium has been described as infecting the human population since its prehistory. This review focuses on the populations and subpopulations of H. pylori, differentiated by the polymorphisms present in their constitutive and virulence genes. These genes have spread and associated with different human populations, showing variability depending on their geographical distribution, and have evolved together with the human being. The predominant genotypes worldwide, Latin America and Chile, are described to understand the genetic diversity and pathogenicity of H. pylori in different populations and geographic regions. The high similarity in the sequence of virulence genes between H. pylori strains present in Peruvian and Spanish natives in Latin America suggests a European influence. The presence of cagA-positive strains and vacA s1 m1 allelic variants is observed with greater prevalence in Chilean patients with more severe gastrointestinal diseases and is associated with its geographical distribution. These findings highlight the importance of understanding the genetic diversity of H. pylori in different regions of the world for a more accurate assessment of the risk of associated diseases and their potential impact on health.

Asunto(s)

Gastritis Atrófica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Proteínas Bacterianas/genética , Helicobacter pylori/genética , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/microbiología , América Latina/epidemiología , Gastritis/patología , Genotipo , Medición de Riesgo , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Antígenos Bacterianos/genética

RESUMEN

Along with Helicobacter pylori infection, the gastric microbiota is hypothesized to modulate stomach cancer risk in susceptible individuals. Whole metagenomic shotgun sequencing (WMS) is a sequencing approach to characterize the microbiome with advantages over traditional culture and 16S rRNA sequencing including identification of bacterial and non-bacterial taxa, species/strain resolution, and functional characterization of the microbiota. In this study, we used WMS to survey the microbiome in extracted DNA from antral gastric biopsy samples from Colombian patients residing in the high-risk gastric cancer town Túquerres (n = 10, H. pylori-positive = 7) and low-risk town of Tumaco (n = 10, H. pylori-positive = 6). Kraken2/Bracken was used for taxonomic classification and abundance. Functional gene profiles were inferred by InterProScan and KEGG analysis of assembled contigs and gene annotation. The most abundant taxa represented bacteria, non-human eukaryota, and viral genera found in skin, oral, food, and plant/soil environments including Staphylococus, Streptococcus, Bacillus, Aspergillus, and Siphoviridae. H. pylori was the predominant taxa present in H. pylori-positive samples. Beta diversity was significantly different based on H. pylori-status, risk group, and sex. WMS detected more bacterial taxa than 16S rRNA sequencing and aerobic, anaerobic, and microaerobic culture performed on the same gastric biopsy samples. WMS identified significant differences in functional profiles found between H. pylori-status, but not risk or sex groups. H. pylori-positive samples were significantly enriched for H. pylori-specific genes including virulence factors such as vacA, cagA, and urease, while carbohydrate and amino acid metabolism genes were enriched in H. pylori-negative samples. This study shows WMS has the potential to characterize the taxonomy and function of the gastric microbiome as risk factors for H. pylori-associated gastric disease. Future studies will be needed to compare and validate WMS versus traditional culture and 16S rRNA sequencing approaches for characterization of the gastric microbiome.

Asunto(s)

Gastritis , Microbioma Gastrointestinal , Infecciones por Helicobacter , Helicobacter pylori , Microbiota , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/microbiología , Colombia , ARN Ribosómico 16S/genética , Infecciones por Helicobacter/microbiología , Gastritis/patología , Helicobacter pylori/genética , Biopsia , Factores de Riesgo , América del Sur

RESUMEN

Stomach pathologies develop in a complex interaction between the host's genetic background and H. pylori virulent genes. Thus, our study aimed to compare active chronic gastritis (ACG), and intestinal metaplasia (IM) with inactive chronic gastritis (ICG), according to interleukin polymorphisms of IL6-174 G/C, IL8-251 A/T, IL1ß-511 C/T, and IL1RN VNTR taking into account patient gender and H. pylori genotypes. Interleukin polymorphisms were determined by RFLP-PCR and H. pylori genotype by PCR. IL6-174 GC and IL8-251 T allele showed a protective effect in women against ACG development and, conversely, IL8-251 polymorphism showed a risk for men. More virulent H. pylori strains were associated with the IL8-251 T allele and IL1ß-511 T allele in the AGC, and the vacA m1 allele and cagE gene from H. pylori was associated with the IM. Analysis of the progression of gastric lesions must take into account host variability genetic associated with genes H. pylori due to the relation between the virulent H. pylori genes and more severe gastric lesions, besides the relevance to the gender to IL6-174 and IL8-251 polymorphisms.

Asunto(s)

Helicobacter pylori , Interleucinas , Polimorfismo Genético , Femenino , Genotipo , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Humanos , Interleucina-6/genética , Interleucina-8/genética , Interleucinas/genética , Masculino , Neoplasias Gástricas/microbiología

RESUMEN

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.

Asunto(s)

Microbioma Gastrointestinal/genética , Neoplasias Gástricas/microbiología , Biología Computacional , Mucosa Gástrica/microbiología , Microbioma Gastrointestinal/fisiología , Helicobacter pylori/genética , Helicobacter pylori/patogenicidad , Humanos , Redes y Vías Metabólicas , Metagenoma , Prevotella/genética , Prevotella/patogenicidad

RESUMEN

PURPOSE: Analyze the expression of caspase-9, Smac/DIABLO, XIAP, let-7a, and let-7b in patients with normal gastric tissue, chronic gastritis, and gastric adenocarcinoma. METHODS: The expression of caspase-9, Smac/DIABLO, XIAP, let-7a, and let-7b by qRT-PCR was analyzed in 158 samples from 53 patients with normal gastric mucosa, 86 with chronic gastritis, and 19 with gastric cancer. RESULTS: The comparison between the gastric cancer and the control group revealed a decreased expression of caspase-9 in gastric cancer tissues; considering the Helicobacter pylor presence, comparable results were revealed. Smac/DIABLO was increased in gastric cancer cells, while XIAP demonstrated no significant difference in the gene expression. The microRNA analysis revealed a decreased expression of let-7a and let-7b in samples positive to H. pylori infection and in gastric cancer group, regardless of the presence of the bacterium. CONCLUSION: Our study provided some evidence of low activity of the intrinsic apoptosis pathway, as well as the influence of H. pylori on let-7a and let-7b expression.

Asunto(s)

Adenocarcinoma/genética , Apoptosis/genética , Biomarcadores de Tumor/genética , Carcinogénesis/genética , Neoplasias Gástricas/genética , Adenocarcinoma/patología , Adulto , Anciano , Proteínas Reguladoras de la Apoptosis/genética , Biopsia , Caspasa 9/genética , Femenino , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis/genética , Gastritis/microbiología , Gastritis/patología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Proteínas Mitocondriales/genética , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Proteína Inhibidora de la Apoptosis Ligada a X/genética

RESUMEN

PURPOSE: The aim of this study was to evaluate the expression of miR-125a-5p in patients with dyspeptic symptoms and gastric cancer, correlating them with the development of this cancer and H. pylori. METHODS: Patients were divided in groups according to histopathological analysis (control, gastritis, and cancer groups). Polymerase chain reaction was performed to detect H. pylori and real-time quantitative PCR to determine miR-125a-5p expression. RESULTS: H. pylori was detected in 44% of the patients, with prevalence in the gastritis and cancer groups. A statistically significant decrease of miR-125a-5p expression was found in the control positive (p = 0.0183*), gastritis positive (p = 0.0380*), and cancer positive (p = 0.0288*) groups when compared with the control negative group. CONCLUSION: We suggest that decreased expression of the miRNA-125a-5p associated with the presence of the H. pylori is an important mechanism in gastric diseases and could be a possible marker for early diagnosis of gastric cancer.

Asunto(s)

Biomarcadores de Tumor/metabolismo , Gastritis/genética , Infecciones por Helicobacter/genética , MicroARNs/metabolismo , Neoplasias Gástricas/genética , Adulto , Anciano , Biomarcadores de Tumor/análisis , Brasil/epidemiología , Línea Celular Tumoral , Proliferación Celular , Detección Precoz del Cáncer/métodos , Femenino , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis/microbiología , Gastritis/patología , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Humanos , Masculino , MicroARNs/análisis , Persona de Mediana Edad , Prevalencia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología

RESUMEN

BACKGROUND & AIMS: Helicobacter pylori eradication and endoscopic surveillance of gastric precancerous lesions are strategies to reduce gastric cancer (GC) risk. To our knowledge, this study is the longest prospective cohort of an H pylori eradication trial in a Hispanic population. METHODS: A total of 800 adults with precancerous lesions were randomized to anti-H pylori treatment or placebo. Gastric biopsy samples taken at baseline and 3, 6, 12, 16, and 20 years were assessed by our Correa histopathology score. A generalized linear mixed model with a participant-level random intercept was used to estimate the effect of H pylori status on the score over time. Logistic regression models were used to estimate progression by baseline diagnosis and to estimate GC risk by intestinal metaplasia (IM) subtype and anatomic location. RESULTS: Overall, 356 individuals completed 20 years of follow-up. Anti-H pylori therapy (intention-to-treat) reduced progression of the Correa score (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.38-0.93). H pylori-negative status had a beneficial effect on the score over time (P = .036). Among individuals with IM (including indefinite for dysplasia) at baseline, incidence rates per 100 person-years were 1.09 (95% CI, 0.85-1.33) for low-grade/high-grade dysplasia and 0.14 (95% CI, 0.06-0.22) for GC. Incomplete-type (vs complete-type) IM at baseline presented higher GC risk (OR, 13.4; 95% CI, 1.8-103.8). Individuals with corpus (vs antrum-restricted) IM showed an OR of 2.1 (95% CI, 0.7-6.6) for GC. CONCLUSIONS: In a high-GC-risk Hispanic population, anti-H pylori therapy had a long-term beneficial effect against histologic progression. Incomplete IM is a strong predictor of GC risk.

Asunto(s)

Antibacterianos/uso terapéutico , Mucosa Gástrica/patología , Infecciones por Helicobacter/tratamiento farmacológico , Lesiones Precancerosas/epidemiología , Neoplasias Gástricas/prevención & control , Adulto , Anciano , Biopsia , Colombia/epidemiología , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Mucosa Gástrica/diagnóstico por imagen , Mucosa Gástrica/microbiología , Gastroscopía/estadística & datos numéricos , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Humanos , Incidencia , Masculino , Metaplasia/diagnóstico , Metaplasia/epidemiología , Metaplasia/microbiología , Metaplasia/patología , Persona de Mediana Edad , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/patología , Estudios Prospectivos , Factores de Riesgo , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Resultado del Tratamiento

RESUMEN

Se determinó la respuesta inmunológica a proteínas recombinantes de Helicobacter pylori en pacientes dis-pépticos (adultos y niños), pacientes con cáncer gástrico y sus familiares asintomáticos adultos viviendo con ellos. Se utilizó la prueba recomLine® Helicobacter IgG e IgA, y con base en el reconocimiento de los factores de virulencia VacA y CagA se determinó si la cepa de H. pylori era de tipo I o II. El análisis de los datos fue descriptivo y analítico y se estimaron los intervalos de confianza de 95%, con un nivel de error de 0.05 y Odds ratio. El 58.7% (121/206) de los pacientes presentó la bacteria en tinción histológica de biopsia, positividad que disminuyó con la edad y daño histológico. La frecuencia de la respuesta a los anticuerpos IgG fue mayor que IgA, en ambos casos ésta fue menor en los niños. Las proteínas del H. pylori más reconocidas tanto por IgA como IgG fueron VacA y CagA, y la respuesta a las otras proteínas investigadas fue mayor al aumentar el daño histológi-co. La cepa tipo I fue la que predominó en la población en estudio con 66% (136/206). Se deben continuar con los estudios de prevalencia de la cepa tipo I del H. pylori y del reconocimiento de sus antígenos en la población guatemalteca a fin de determinar su utilidad en el diagnóstico y pronóstico de la infección.

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The immune response to recombinant Helicobacter pylori proteins was determined in dyspeptic patients (adults and children), patients with gastric cancer and their asymptomatic adults' relatives living with them. The recomLine® Helicobacter IgG and IgA test was used and based on the recognition of the virulence factors VacA and CagA, it was determined whether the H. pylori strain was type I or II. The data analysis was descriptive and analytic, and 95% confidence intervals were estimated, with an error level of 0.05, and Odds ratio. The patients that presented the bacterium in histological biopsy were 58.7% (121/206), positivity that decreased with age and histological damage. The frecuency of response to IgG antibodies was higher than IgA, in both cases it was lower in children. VacA and CagA were the H. pylori proteins most recognized by both IgA and IgG and it was observed that the number of recognized proteins was greater with increasing histological damage. The type I strain was the one that predominated in the study population 66% (136/206). Prevalence studies of the type I strain of H. pylori ant the recognition of its antigens in the Guatemalan population should continue in order to determine its usefulness in the diagnosis and prognosis of infection.

Asunto(s)

Humanos , Niño , Adulto , Neoplasias Gástricas/inmunología , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Helicobacter pylori/inmunología , Dispepsia/inmunología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Biopsia , Proteínas Recombinantes/análisis , Proteínas Recombinantes/inmunología , Inmunoglobulina A/análisis , Inmunoglobulina G/análisis , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/patogenicidad , Dispepsia/microbiología , Dispepsia/patología , Guatemala

RESUMEN

Chronic inflammation resulting from Helicobacter pylori (H. pylori) infection, the major risk factor for gastric cancer, results in increased release of reactive oxygen species (ROS), promoting oxidative stress and DNA damage. APE1 endonuclease, a key component of the base excision repair (BER) pathway, is responsible for the repair of damage induced by ROS. However, the APE1 gene and other DNA damage response (DDR) genes are still poorly understood in gastric cancer. Thus, we aimed to investigate whether the silencing of APE1 by shRNA can interfere with the survival of AGS gastric cancer cells after treatment with hydrogen peroxide (H2O2) and/or H. pylori extract (HPE) and its relation with the expression of DDR genes (ATM, ATR, and H2AX) and miRNAs that target DDR genes. In the AGS cells expressing APE1, isolated or combined treatment with H2O2 and HPE promoted a slight increase in the cell proliferation and increased the levels of intracellular ROS and DNA double strand breaks (DSBs) indicated by ©H2AX foci, a reduction in the proportion of cells in the G0/G1 phase and an increase in the initial apoptosis rate. Moreover, upregulation of APE1, ATR, miR-15a, miR-21, miR-24 and miR-421 and downregulation of ATM and H2AX was observed. In silenced AGS cells after treatment with H2O2 alone or combined with HPE, we observed an increase in the cell proliferation rate and the levels of intracellular ROS and DSBs and a reduction in the proportion of cells in S and G2/M phase arrest, leading to late apoptosis. APE1 knockdown also caused a reduction in the expression of ATM and miR-421, while ATR expression was increased. Based on our results, APE1 knockdown may promote changes in cellular processes by increasing genomic instability, leading to G2/M arrest and cell apoptosis, so it may be a promising strategy for controlling tumor progression.

Asunto(s)

Apoptosis , Reparación del ADN , ADN-(Sitio Apurínico o Apirimidínico) Liasa/genética , Puntos de Control de la Fase G2 del Ciclo Celular , Helicobacter pylori , Peróxido de Hidrógeno/toxicidad , Neoplasias Gástricas/fisiopatología , Proteínas de la Ataxia Telangiectasia Mutada/genética , Línea Celular Tumoral , Proliferación Celular , Roturas del ADN de Doble Cadena , Daño del ADN , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Histonas , Humanos , Peróxido de Hidrógeno/farmacología , MicroARNs/genética , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/terapia

RESUMEN

Aim:Helicobacter pylori is usually detected based on hematoxylin-eosin (H-E) features, but, immunohistochemistry (IHC) and real-time PCR (RT-PCR) are more precise in chronic-gastritis. We evaluated the relevance of these tests in Peruvian gastric cancer samples. Materials & methods: We performed and evaluated H-E, IHC staining and RT-PCR in 288 gastric tumors. Slides were independently evaluated by three pathologists. Results:H. pylori was detected in 167/287 through H-E, 140/288 through IHC and 175/288 through RT-PCR, and positive-status were associated (p < 0.001). H. pylori detection by H-E had a good concordance with IHC (kappa index = 0.632) but poor with RT-PCR (kappa index = 0.317). Higher median gene-copies were found in high H. pylori density through H-E or IHC (p < 0.001). Conclusion: H-E evaluation is accurate in gastric cancer, and IHC and RT-PCR can complement its results.

Asunto(s)

Helicobacter pylori/aislamiento & purificación , Técnicas Histológicas/métodos , Inmunohistoquímica/métodos , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Helicobacter pylori/clasificación , Helicobacter pylori/genética , Humanos , Masculino

RESUMEN

BACKGROUND: Regional variations in gastric cancer incidence are not explained by prevalence of Helicobacter pylori, the main cause of the disease, with several areas presenting high H. pylori prevalence but low gastric cancer incidence. The IARC worldwide H. pylori prevalence surveys (ENIGMA) aim at systematically describing age and sex-specific prevalence of H. pylori infection around the world and generating hypotheses to explain regional variations in gastric cancer risk. METHODS: We selected age- and sex-stratified population samples in two areas with different gastric cancer incidence and mortality in Chile: Antofagasta (lower rate) and Valdivia (higher rate). Participants were 1-69 years old and provided interviews and blood for anti-H. pylori antibodies (IgG, VacA, CagA, others) and atrophy biomarkers (pepsinogens). RESULTS: H. pylori seroprevalence (Age-standardized to world population) and antibodies against CagA and VacA were similar in both sites. H. pylori seroprevalence was 20% among children <10 years old, 40% among 10-19 year olds, 60% in the 20-29 year olds and close to or above 80% in those 30+ years. The comparison of the prevalence of known and potential H. pylori cofactors in gastric carcinogenesis between the high and the low risk area showed that consumption of chili products was significantly higher in Valdivia and daily non-green vegetable consumption was more common in Antofagasta. Pepsinogen levels suggestive of gastric atrophy were significantly more common and occurred at earlier ages in Valdivia, the higher risk area. In a multivariate model combining both study sites, age, chili consumption and CagA were the main risk factors for gastric atrophy. CONCLUSIONS: The prevalence of H. pylori infection and its virulence factors was similar in the high and the low risk area, but atrophy was more common and occurred at younger ages in the higher risk area. Dietary factors could partly explain higher rates of atrophy and gastric cancer in Valdivia. IMPACT: The ENIGMA study in Chile contributes to better understanding regional variations in gastric cancer incidence and provides essential information for public health interventions.

Asunto(s)

Infecciones por Helicobacter/complicaciones , Helicobacter pylori/aislamiento & purificación , Neoplasias Gástricas/etiología , Estómago/patología , Adolescente , Adulto , Anciano , Atrofia/etiología , Atrofia/microbiología , Atrofia/patología , Niño , Preescolar , Chile/epidemiología , Femenino , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Humanos , Lactante , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Estómago/microbiología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Adulto Joven

RESUMEN

It is known that Helicobacter pylori is the main cause of peptic ulceration and gastric cancer. However, there is a lack of information on whether H. pylori strains may differ in gastric cancer histological subtypes. This study aimed to investigate different H. pylori strains considering six cag Pathogenicity Island - cagPAI genes (cagA, cagE, cagG, cagM, cagT, and virb11), and vacuolating cytotoxin - vacA alleles, and their relation to gastric cancer histologic subtypes. For this purpose, tumor samples from 285 patients with gastric carcinoma were used. H. pylori infection and genotypes were determined by polymerase chain reaction (PCR). H. pylori was detected in 93.9% of gastric tumors. For comparative analyzes between histopathological subtypes considering H. pylori cagPAI genes the strains were grouped according to the vacA s1/s2 alleles. In the vacAs1 group, the strains cagA(-)cagE(+), cagA(+)cagE(+)cagG(+), cagA(+)cagM(+), or only cagE(+) strains were more frequent in the intestinal subtype (P = .009; P = .024; P = .046, respectively). In contrast, cagM(+)cagG(+)cagA(-) and cagE(-) were associated with diffuse tumors (P = .036), highlighting the presence of cagE in the development of intestinal tumors, and the presence of cagG and absence of cagE in diffuse tumors. Furthermore, WEKA software and Decision Tree (CART) analyses confirmed these findings, in which cagE presence was associated with intestinal tumors, and cagE absence and cagG(+) with diffuse tumors. In conclusion our results showed that vacAs1 (cagG + cagM) strains, mainly cagG positive with cagE absence, were relevant in the studied population for the diffuse outcome, while the presence of cagE was relevant for the intestinal outcome. These findings suggest the relevance of these H. pylori genes as potential markers for gastric cancer histological outcomes.

Asunto(s)

Proteínas Bacterianas/metabolismo , Biomarcadores , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/metabolismo , Neoplasias Intestinales/microbiología , Neoplasias Gástricas/microbiología , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Bacterianas/genética , Carcinoma/microbiología , Femenino , Genes Bacterianos , Infecciones por Helicobacter/microbiología , Humanos , Neoplasias Intestinales/complicaciones , Neoplasias Intestinales/patología , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/patología , Adulto Joven

RESUMEN

Helicobacter pylori (Hp) infects the stomach of about half of the human population and is strongly associated with the risk of gastric cancer (GC) and its premalignant precursors. The cag pathogenicity island (cagPAI) is a region of the Hp genome encoding for key molecular machinery involved in the infection process. Following a sequencing study, we selected 50 genetic polymorphisms located in seven cagPAI genes and tested their associations with the risk of advanced gastric premalignant lesions and GC in 1220 subjects from various Latin American populations showing the whole spectrum of phenotypes from gastritis to GC. We found that three polymorphisms of cagA are associated with the risk of advanced gastric premalignant lesions (incomplete intestinal metaplasia [ie, Type 2 and 3] or dysplasia), and that six polymorphisms located in cagA, cagL and cagI were associated with risk of GC. When corrected for multiple testing none of the associations were statistically significant. However, scores built by integrating the individual polymorphisms were significantly associated with the risk of advanced gastric premalignant lesions and GC. These results have the potential of establishing markers for risk stratification in the general population, in view of targeting Hp eradication to high-risk population groups.

Asunto(s)

Mucosa Gástrica/patología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Lesiones Precancerosas/microbiología , Neoplasias Gástricas/epidemiología , Adulto , Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Biopsia , Colombia/epidemiología , ADN Bacteriano/genética , ADN Bacteriano/aislamiento & purificación , Femenino , Mucosa Gástrica/microbiología , Gastritis/microbiología , Gastritis/patología , Marcadores Genéticos , Genoma Bacteriano/genética , Islas Genómicas , Infecciones por Helicobacter/patología , Helicobacter pylori/aislamiento & purificación , Helicobacter pylori/patogenicidad , Humanos , Masculino , Metaplasia/microbiología , Metaplasia/patología , México/epidemiología , Persona de Mediana Edad , Polimorfismo Genético , Lesiones Precancerosas/patología , Medición de Riesgo/métodos , Factores de Riesgo , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Secuenciación Completa del Genoma

RESUMEN

Helicobacter pylori (H. pylori) is one of the main causes of gastric gancer. TNF-related apoptosis-inducing ligand (TRAIL) is a protein able to promote apoptosis in cancer cells, however not in gastric cancer, which presents resistance to apoptosis via TRAIL. It is believed that MicroRNA-106b-5p might be involved in this resistance, although its role in Gastric Cancer is unclear. We aimed to determine the expression of microRNA-106b-5p and TRAIL in patients with gastric diseases, infected by H. pylori, and understand the relationship between these genes and their role in apoptosis and the gastric cancer pathways. H. pylori was detected by PCR, gene expression analysis was performed by real-time-qPCR, and bioinformatics analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cytoscape software. A total of 244 patients were divided into groups (Control, Gastritis, and Cancer); H. pylori was detected in 42.2% of the samples. The cancer group had a poor expression of TRAIL (p < 0.0001) and overexpression of microRNA-106b-5p (p=0.0005), however, our results confirmed that these genes are not directly related to each other although both are apoptosis-related regulators. Our results also indicated that H. pylori decreases microRNA-106b-5p expression and that this is a carcinogenic bacterium responsible for gastric diseases.

Asunto(s)

Infecciones por Helicobacter/genética , MicroARNs/genética , Neoplasias Gástricas/genética , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Apoptosis/genética , Femenino , Gastritis/genética , Gastritis/microbiología , Gastritis/patología , Regulación Neoplásica de la Expresión Génica/genética , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/genética , Helicobacter pylori/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Transducción de Señal/genética , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología

RESUMEN

Infection by Helicobacter pylori is a major risk factor for gastric cancer (GC), the second leading cause of cancer-related death worldwide. Although biomarkers such as pepsinogens (PGs) and soluble urokinase plasminogen activator receptor (suPAR) may have diagnostic and/or prognostic value in patients with GC, their levels may be affected by H. pylori infection. The aim of this study was to investigate the association of the presence of antibodies to H. pylori and cytotoxin-associated gene A (CagA) with plasma levels of PGs and suPAR in a cohort of Guatemalan GC patients and controls. To this end, levels of suPAR, Pepsinogens I and II (PGI and PGII), and antibodies to H. pylori and CagA toxin were determined by ELISA in plasma samples from 67 GC patients and 136 matched healthy controls. Seropositivity for CagA was significantly higher in patients with GC than in controls. Pepsinogens II and suPAR levels were higher and PGI/PGII ratios were lower in GC patients than in controls. There was a significant association of H. pylori seropositivity status with increased levels of PGII and lower PGI/PGII ratios, particularly in the control (non-GC) population. The levels of suPAR were not significantly affected by H. pylori or CagA seropositivity status. These results suggest that the seropositivity status for H. pylori and CagA need to be taken into account during the GC diagnostic process.

Asunto(s)

Antígenos Bacterianos/inmunología , Proteínas Bacterianas/inmunología , Infecciones por Helicobacter/epidemiología , Helicobacter pylori/inmunología , Pepsinógeno A/sangre , Receptores del Activador de Plasminógeno Tipo Uroquinasa/sangre , Neoplasias Gástricas/microbiología , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Guatemala/epidemiología , Infecciones por Helicobacter/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Estudios Seroepidemiológicos , Neoplasias Gástricas/sangre

RESUMEN

Helicobacter pylori is a Gram-negative bacterium that causes chronic atrophic gastritis and peptic ulcers and it has been associated with the development of gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT). One of the more remarkable characteristics of H. pylori is its ability to survive in the hostile environment of the stomach. H. pylori regulates the expression of specific sets of genes allowing it to survive high acidity levels and nutrient scarcity. In the present study, we determined the expression of virulence associated protein D (VapD) of H. pylori inside adenocarcinoma gastric (AGS) cells and in gastric biopsies. Using qRT-PCR, VapD expression was quantified in intracellular H. pylori-AGS cell cultures at different time points and in gastric mucosa biopsies from patients suffering from chronic atrophic gastritis, follicular gastritis, peptic ulcers, gastritis precancerous intestinal metaplasia and adenocarcinoma. Our results show that vapD of H. pylori presented high transcription levels inside AGS cells, which increased up to two-fold above basal values across all assays over time. Inside AGS cells, H. pylori acquired a coccoid form that is metabolically active in expressing VapD as a protection mechanism, thereby maintaining its permanence in a viable non-cultivable state. VapD of H. pylori was expressed in all gastric biopsies, however, higher expression levels (p = 0.029) were observed in gastric antrum biopsies from patients with follicular gastritis. The highest VapD expression levels were found in both antrum and corpus gastric biopsies from older patients (>57 years old). We observed that VapD in H. pylori is a protein that is only produced in response to interactions with eukaryotic cells. Our results suggest that VapD contributes to the persistence of H. pylori inside the gastric epithelial cells, protecting the microorganism from the intracellular environment, reducing its growth rate, enabling long-term infection and treatment resistance.

Asunto(s)

Proteínas Bacterianas/genética , Gastritis Atrófica/etiología , Helicobacter pylori/genética , Glicoproteínas de Membrana/genética , Estómago/microbiología , Estómago/patología , Adenocarcinoma/etiología , Adenocarcinoma/microbiología , Adenocarcinoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Técnicas de Cocultivo/métodos , Femenino , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis Atrófica/microbiología , Gastritis Atrófica/patología , Gastroscopía/métodos , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/patología , Humanos , Intestinos/microbiología , Intestinos/patología , Masculino , Metaplasia/microbiología , Metaplasia/patología , Persona de Mediana Edad , Úlcera Péptica/metabolismo , Úlcera Péptica/patología , Lesiones Precancerosas/etiología , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/patología , Antro Pilórico/microbiología , Antro Pilórico/patología , Neoplasias Gástricas/etiología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Virulencia/genética , Adulto Joven