Helicobacter pylori induces gastric cancer via down‐regulating miR‐375 to inhibit dendritic cell maturation

Abstract

Background: Recent studies and clinical samples have demonstrated that Helicobacter pylori could induce the downregulation of miR-375 in the stomach and promote gastric carcinogenesis. However, whether the immune cells are affected by Helicobacter pylori due to the downregulation of miR-375 is unclear. Materials and methods:In this study, we constructed an overexpression and knockdown of miR-375 and Helicobacter pylori infection cell models in vitro. In addition, the maturity of dendritic cells (DCs) and the expression of IL-6, IL-10, and VEGF at the transcriptional and translational levels were analyzed. Changes in the JAK2-STAT3 signaling pathway were detected. In vivo, the number changes in CD4+ T and CD8+ T cells and the size changes of tumors via models of transplantable subcutaneous tumors were also analyzed. Results: A cell model of Helicobacter pylori and gastric cancer was used to identify the expression of miR-375 and the maturity of dendritic cells. This study found that Helicobacter pylori could downregulate miR-375, which regulates the expression of cytokines IL-6, IL-10, and VEGF in the stomach. MiR-375 regulated the expression of cytokines IL-6, IL-10, and VEGF through the JAK2-STAT3 signaling pathway in vitro. In addition, we found that Helicobacter pylori regulates the maturation of dendritic cells through miR-375. These results were further verified in vivo, and miR-375 diminishes tumor size was also demonstrated. This study showed that immature DCs caused a decrease in the number of CD4+ and CD8+ T cells. Conclusions: This study demonstrated that Helicobacter pylori can inhibit miRNA-375 expression in the stomach. Downregulated miR-375 activates the JAK2-STAT3 pathway. Activating the JAK2-STAT3 signaling pathway promotes the secretion of IL-6, IL-10, and VEGF, leading to immature differentiation of DCs and induction of gastric cancer.

miR-107 Inhibits the Proliferation of Gastric Cancer Cells In vivo and In vitro by Targeting TRIAP1

“…Although there are treatments for this type of cancer, the recurrence is frequent and the treatment has many side effects. Therefore, it is necessary to explore new drugs or determine specific therapeutic targets for the treatment of gastric cancer ( Hurwitz et al, 2020 ; Zhang et al, 2021 ). Over the years, a series of miRNAs have been found to be dysregulated in a variety of cancer cells and are associated with cancer progression.…”

“…Gastric cancer (GC) is a common malignant tumor with a high recurrence index and a high recurrence rate, with a mortality rate as high as 40% ( Hurwitz et al, 2020 ). Although great progress has been made in the treatment of GC, the 5-year survival rate of patients diagnosed with metastatic GC is less than 20% ( Anauate et al, 2017 ; Zhang et al, 2021 ), and the in-depth study of the pathogenesis of GC, new molecular markers and therapeutic targets are of great significance to its diagnosis and treatment.…”

Emerging Role of Helicobacter pylori in the Immune Evasion Mechanism of Gastric Cancer: An Insight Into Tumor Microenvironment-Pathogen Interaction

“…MiR-375 expression is frequently decreased in gastric carcinoma as well as weakens cell proliferation through targeting JAK2 oncogene. H. pylori infection downregulates its expression in gastric cancer cells and promotes the release of cytokines IL-6, IL-10, and VEGF via the JAK2-STAT3 signaling, and thus induces the maturation of dendritic cells and the reduction in the number of CD4+ and CD8+ T cells ( 23 ).…”

Relação do H. pylori com o desenvolvimento do câncer gástrico: revisão sistemática / Relationship of H. pylori to the development of gastric cancer: a systematic review

“…Brazilian Journal of Development, Curitiba, v.7, n.12, p. 114228-114233 dec. 2021 O câncer gástrico se desenvolve através do acúmulo de lesões sobre o epitélio gástrico formando a massa neoplásica, ou seja, a evolução do tumor começa de modo lento e silencioso e se o diagnóstico não for realizado de maneira precoce ocorre a progressão de forma rápida, podendo atingir camadas mais profundas do estômago; além da ocorrência de metástase nos linfonodos regionais e também por contiguidade, sinalizando que o tumor atingiu os órgãos vizinhos (OLIVEROS et al, 2019;INCA, 2018). ZHANG et al (2021), demonstraram que Helicobacter pylori pode inibir a expressão do miRNA-375 no estômago. O miR-375 regulado, ativa a via JAK2-STAT3 promovendo a secreção de IL-6, IL-10 e VEGF (fator de crescimento endotelial vascular) levando à diferenciação imatura das células dendríticas e à indução de câncer gástrico.…”

“…Atualmente, vem se buscando alguns marcadores moleculares que possam ajudar no entendimento da patogênese do câncer gástrico relacionado à H. pylori. Talvez marcadores como os micro RNAs (miR) que participam da regulação da expressão gênica como é o caso do miRNA-375 no estômago levando à diferenciação imatura das células dendríticas e à indução de câncer gástrico(ZHANG et al, 2021) possa a ajudar na compreensão.Em razão dos fatos percebe-se que o tema tem uma grande importância atualmente, já que possui publicações relevantes que foram publicadas recentemente, mesmo que o H. pylori seja comum apenas em países em desenvolvimento e em muitos locais já ocorreu sua erradicação, ainda continua sendo o principal causador do câncer gástrico que é o quinto tumor mais frequente em meio a população.É possível observar que 86,7% dos estudos confirmam este fato, mesmo existindo outros fatores que possam levar ao desenvolvimento deste tipo de câncer a bactéria ainda é a mais prevalente. Os 13,3% que não estabelecem a relação podem sofrer variações por conta da população de estudo, onde a amostra pode ser pequena.…”