Helicobacter pylori is closely associated with gastric cancer. During persistent infection, Helicobacter pylori can form a microenvironment in gastric mucosa which facilitates the survival and colony formation of Helicobacter pylori. Tumor stromal cells are involved in this process, including tumor-associated macrophages, mesenchymal stem cells, cancer-associated fibroblasts, and myeloid-derived suppressor cells, and so on. The immune checkpoints are also regulated by Helicobacter pylori infection. Helicobacter pylori virulence factors can also act as immunogens or adjuvants to elicit or enhance immune responses, indicating their potential applications in vaccine development and tumor immunotherapy. This review highlights the effects of Helicobacter pylori on the immune microenvironment and its potential roles in tumor immunotherapy responses.

Histone deacetylase inhibitors (HDACis) are a new class of anticancer drugs confirmed to have good therapeutic effects against gastric cancer (GC) in preclinical experiments, but most HDACis are non-selective (pan-HDACis), with highly toxic side effects. Therefore, it is necessary to screen HDAC family members that play key roles in GC as therapeutic targets to reduce toxic side effects. In this study, we evaluated the targeting specificity of the HDACi suberoylanilide hydroxamic acid (SAHA) for GC via fluorescence molecular imaging (FMI). In vitro FMI results showed that SAHA had higher binding affinity for GC cells than for normal gastric cells. In vivo FMI of gastric tumor-bearing mice confirmed that SAHA can be enriched in GC tissues. However, there was also a high-concentration distribution in normal organs such as the stomach and lungs, suggesting potential side effects. In addition, we found that among the HDAC family members, HDAC9 was the most significantly upregulated in GC cells, and we verified this upregulation in GC tissues. Further experiments confirmed that knockdown of HDAC9 inhibits cell growth, reduces colony formation, and induces apoptosis and cell cycle arrest. These results suggest that HDAC9 has an oncogenic role in GC. Moreover, HDAC9 siRNA suppressed GC tumor growth and enhanced the antitumor efficacy of cisplatin in GC treatment by inhibiting the proliferation and inducing the apoptosis of GC cells in vitro and in vivo. Our findings suggest that the development of HDAC9-selective HDACis is a potential approach to improve the efficacy of chemotherapy and reduce systemic toxicity.

Gastric cancer is an important cause of death worldwide with Helicobacter pylori (H. pylori) considered a leading and known risk factor for its development. More particularly and despite the underlying mechanisms not being very clear, studies have revealed that the H. pylori cytotoxin-associated gene A (CagA) protein plays a key role in this process. In this study it was found that H. pylori increased the expression of miR-543 in human gastric cancer tissue when compared with H. pylori-negative gastric cancer tissue samples. In vitro experiments showed that increased expression of miR-543 induced by CagA is a strong promoter of cell proliferation, migration, and invasion. Conversely, a miR-543 inhibitor suppressed or reversed these effects. It was furthermore found that silencing miR-543 inhibited autophagy and led to epithelial–mesenchymal transition (EMT) under in vitro. The mechanisms by which miR-543 targets SIRT1 to downregulate autophagy was also described. The results suggest that in the progression of H. pylori-associated gastric cancer, CagA induces overexpression of miR-543, which subsequently targets SIRT1 to suppress autophagy. This may be followed by increased expression of EMT causing cell migration and invasion. Consequently, miR-543 might be considered a therapeutic target for H. pylori-associated gastric cancer.

Microbiome changes in the gastric mucosa and gastric juice in different histological stages of Helicobacter pylori-negative gastric cancers

Background: Abnormal DNA methylation is a hallmark of human cancers and may be a promising biomarker for early diagnosis of human cancers. However, the majority of DNA methylation biomarkers that have been identified are based on the hypothesis that early differential methylation regions (DMRs) are maintained throughout carcinogenesis and could be detected at all stages of cancer. Methods: In this study, we identified potential early biomarkers of colorectal cancer (CRC) development by genome-wide DNA methylation assay (Illumina infinium450, 450 K) of normal (N = 20) and pre-colorectal cancer samples including 18 low-grade adenoma (LGA) and 22 high-grade adenoma (HGA), integrated with GEO and ArrayExpress datasets (N = 833). Results: We identified 209 and 8692 CpG sites that were significantly hyper-methylated in LGA and HGA, respectively. Pathway analysis identified nervous system-related methylation changes that are significantly associated with early adenoma development. Integration analysis revealed that DNA methylation in the promoter region of ADHFE1 has the most potential for being an early diagnostic biomarker for colorectal adenoma and cancer (sensitivity = 0.96, specificity = 0.95, area under the curve = 0.97). Conclusions: Overall, we demonstrated that DNA methylation have been shown significant changes in the stage of LGA and HGA in the development of colon cancer. Genome-wide DNA methylation to LGA and HGA provided an important proxy to identify promising early diagnosis biomarkers for colorectal cancer.