RESUMEN
Matrix metalloproteinases (MMPs) play key roles in epithelial-mesenchymal transition (EMT) for the development of cancer cell invasion and metastasis. MMP-13 is an extracellular matrix (ECM)-degrading enzyme that plays crucial roles in angiogenesis, cell cycle regulation, niche maintenance, and transforming squamous epithelial cells in various tissues. CD44, a transmembrane glycoprotein expressed on esophageal tumor cells, is required for EMT induction and invasion in esophageal squamous cell carcinoma (ESCC). The transcription factor TWIST1, as EMT and stemness marker, regulates MMPs expression and is identified as the downstream target of CD44. In this study, we aimed to investigate the probable interplay between the expression of key genes contributing to ESCC development, including MMP-13, TWIST1, and CD44 with clinical features for introducing novel diagnostic and therapeutic targets in the disease. The gene expression profiling of MMP-13, TWIST1, and CD44 was performed using quantitative real-time PCR in tumor tissues from 50 ESCC patients compared to corresponding margin non-tumoral tissues. Significant overexpression of MMP-13, CD44S, CD44V3, CD44V6, and TWIST1 were observed in 74%, 36%, 44%, 44%, and 52% of ESCC tumor samples, respectively. Overexpression of MMP-13 was associated with stage of tumor progression, metastasis, and tumor location (P < 0.05). There was a significant correlation between TWIST1 overexpression and grade (P < 0.05). Furthermore, overexpression of CD44 variants was associated with stage of tumor progression, grade, tumor invasion, and location (P < 0.05). The results indicated the significant correlation between concomitant expression of MMP-13/TWIST1, TWIST1/CD44, and CD44/MMP-13 with each other in a variety of clinicopathological traits, including depth of tumor invasion, tumor location, stage of tumor, and lymph node involvement in ESCC tissue samples (P < 0.05). Collectively, our results indicate that the TWIST1-CD44-MMP-13 axis is involved in tumor aggressiveness, proposing these genes as regulators of EMT, diagnostic markers, and therapeutic targets in ESCC.
Asunto(s)
Transición Epitelial-Mesenquimal , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/metabolismo , Receptores de Hialuranos/metabolismo , Metaloproteinasa 13 de la Matriz/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteína 1 Relacionada con Twist/metabolismo , Anciano , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Femenino , Humanos , Receptores de Hialuranos/genética , Masculino , Metaloproteinasa 13 de la Matriz/genética , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteína 1 Relacionada con Twist/genéticaRESUMEN
Preclinical models are extensively employed in cancer research because they can be manipulated in terms of their environment, genome, molecular biology, organ systems, and physical activity to mimic human behavior and conditions. The progress made in in vivo cancer research has resulted in significant advancements, enabling the creation of spontaneous, metastatic, and humanized mouse models. Most recently, the remarkable and extensive developments in genetic engineering, particularly the utilization of CRISPR/Cas9, transposable elements, epigenome modifications, and liquid biopsies, have further facilitated the design and development of numerous mouse models for studying cancer. In this review, we have elucidated the production and usage of current mouse models, such as xenografts, chemical-induced models, and genetically engineered mouse models (GEMMs), for studying esophageal cancer. Additionally, we have briefly discussed various gene-editing tools that could potentially be employed in the future to create mouse models specifically for esophageal cancer research.
Asunto(s)
Neoplasias Esofágicas , Edición Génica , Animales , Ratones , Humanos , Edición Génica/métodos , Ingeniería Genética , Modelos Animales de Enfermedad , Neoplasias Esofágicas/genéticaRESUMEN
BACKGROUND: The appendix is considered as part of the gut-associated lymphoid tissue; however, lymphocyte subsets in this tissue are not fully defined. OBJECTIVE: To investigate and compare the function and phenotype of lymphocyte subsets in peripheral blood and appendix of patients with normal and inflamed appendix tissues. METHODS: Peripheral blood samples and appendiceal mononuclear cells were obtained from 81 patients (mean age; 23 ± 10.5 years), clinically suspected of having appendicitis. The phenotypic characteristics of lymphocyte subsets in peripheral blood (before and 48-72 hrs after appendectomy) and in appendix tissue were analyzed by three color-flow cytometry. The proliferative response of mononuclear cells was assessed by MTT method. RESULTS: The frequency of CD19+DR+, HLA-DR+ and CD19+ cells in the appendix tissue were significantly higher than that of the peripheral blood in all the groups (p<0.001). The percentage of CD19+ cells and HLA-DR+CD19+ cells significantly decreased after appendectomy in the peripheral blood of the patients with acute appendicitis (p=0.047 and p=0.03, respectively). CD19 and HLA-DR plus CD19 had better diagnostic efficiency compared with T cell markers (area under the ROC curve [AUC]= 0.76 and 0.73, respectively). CONCLUSION: These results indicate a significant difference in CD19+ and HLA-DR+ lymphocytes between peripheral blood and the appendix tissue.