ABSTRACT
ABSTRACT Background: Early-onset diffuse gastric cancer (EODGC) occurs at or before 50 years of age. Pathogenic mutations and germline deletions in the CDH1 gene (E-cadherin) are well-documented genetic factors associated with the causes of EODGC. Objective: The objective of the study was to study CDH1 germline variants and their potential functional impact in patients with EODGC in a Mexican population. Methods: We studied seven EODGC patients from a biomedical research center in western Mexico. Variants were identified by Sanger sequencing and multiplex ligation-dependent probe amplification. The DeepSEA and SNPClinic v.1.0 software and the Ensembl (1000 Genomes Project, 1kGP) and ClinVar databases were used to predict functional single-nucleotide polymorphisms (SNPs). The genetic admixture of the Mexican patients was corroborated by 22 short tandem repeat loci genotyping and structure analysis. Results: We found 12 germline CDH1 variants in all EODGC patients, and all of them are considered as polymorphisms: rs34561447, rs5030625, rs16260, rs1330727101, rs28372783, rs942269593, rs3743674, rs1801552, rs34939176, rs33964119, rs3556654, and rs1801026. The prediction of regulatory SNPs in the promoter suggests a role for a retrovirus in EODGC that induces the transcription of interferon-related genes through toll-like receptor-interferon response factor 3 signaling, as three SNPs in the CDH1 promoter alter three binding sites for this transcription factor. In addition, SNPs rs28372783 and rs1801026 could alter upstream stimulatory factors 1 (USF1)/USF2-mediated telomerase-dependent lymphocyte activation in EODGC. Other interesting result is a CTCF-dependent shorter CDH1 isoform lacking exon 14, probably due to exon-skipping mediated by rs33964119. Conclusions: Classical pathogenic germline mutations in the CDH1 gene were not found in these 7 EODGC patients. However, the in silico approaches revealed the possible involvement of a retrovirus and a shorter E-cadherin isoform in EODGC. Nevertheless, further in vitro and in vivo assays are needed to confirm these predictions.
ABSTRACT
Los inconvenientes del tratamiento con antibióticos, como el surgimiento de cepas multirresistentes y las reacciones adversas, han llevado a la búsqueda de alternativas. El conocimiento de las rutas de activación de la respuesta inmune innata y sus interacciones con las rutas de señalización de la respuesta inmune adaptativa podría llevar a tratamientos basados en elicitores de péptidos antimicrobianos, sustancias inocuas que producen la sobreexpresión de genes de la respuesta inmune innata, más efectivos, rápidos y seguros para combatir las infecciones, que siguen siendo un problema de salud pública mundial.
The drawbacks associated with antibiotic-based treatment of infectious diseases including an increase in multidrug-resistant strains and adverse reactions have lead to the search of antimicrobial peptide elicitors (APE), harmless substances that boost an overexpression of innate immunity genes. Knowledge on innate immunity activation pathways and their interactions with adaptive immunity would lead to more effective, faster and safer APE-based treatments to battle infections which still are a common public health problem worldwide.
Subject(s)
Humans , Bacterial Infections/drug therapy , Bacterial Infections/immunology , Antimicrobial Cationic Peptides/therapeutic useABSTRACT
Las defensinas humanas son péptidos antimicrobianos de síntesis endógena, con potencial profiláctico y terapéutico anti VIH. La aplicación de las defensinas como agentes tópicos en mucosas expuestas podría bloquear la entrada del VIH, debido a la capacidad de estos péptidos de unirse a la envoltura viral. Además, la capacidad de las defensinas para inhibir la replicación del virus, activar el sistema del complemento y quimiotaxis hacia células dendríticas y células T de memoria, permitirá diseñar mejores drogas antiretrovirales, siendo necesario evaluar la eficacia de las defensinas en la práctica clínica.
Human defensins are endogenous antimicrobial peptides with prophylactic and therapeutic potential against HIV. The ability of defensins to bind the HIV envelope could be exploited to design topic agents that block viral entry into exposed mucosa. Additionally, their capacity to inhibit viral replication, complement system activation, dendritic and memory T cells chemoattraction, together with peptide engineering could bring about new and better antiretroviral drugs. Clinical trials could be demonstrated the efficacy of defensins against HIV in clinical practice.