Abstract
Emerging evidence suggests that chronic inflammation caused by pathogen infection is connected to the development of various types of cancer. It is estimated that up to 20% of all cancer deaths is linked to infections and inflammation. In gastric cancer, such triggers can be infection of the gastric epithelium by either Helicobacter pylori (H. pylori), a bacterium present in half of the world population; or by Epstein-Barr virus (EBV), a double-stranded DNA virus which has recently been associated with gastric cancer. Both agents can establish lifelong inflammation by evolving to escape immune surveillance and, under certain conditions, contribute to the development of gastric cancer. Non-coding RNAs, mainly microRNAs (miRNAs), influence the host innate and adaptive immune responses, though long non-coding RNAs and viral miRNAs also alter these processes. Reports suggest that chronic infection results in altered expression of host miRNAs. In turn, dysregulated miRNAs modulate the host inflammatory immune response, favoring bacterial survival and persistence within the gastric mucosa. Given the established roles of miRNAs in tumorigenesis and innate immunity, they may serve as an important link between H. pylori- and EBV-associated inflammation and carcinogenesis. Example of this is up-regulation of miR-155 in H. pylori and EBV infection. The tumor environment contains a variety of cells that need to communicate with each other. Extracellular vesicles, especially exosomes, allow these cells to deliver certain type of information to other cells promoting cancer growth and metastasis. Exosomes have been shown to deliver not only various types of genetic information, mainly miRNAs, but also cytotoxin-associated gene A (CagA), a major H. pylori virulence factor. In addition, a growing body of evidence demonstrates that exosomes contain genetic material of viruses and viral miRNAs and proteins such as EBV latent membrane protein 1 (LMP1) which are delivered into recipient cells. In this review, we focus on the dysregulated H. pylori- and EBV-associated miRNAs while trying to unveil possible causal mechanisms. Moreover, we discuss the role of exosomes as vehicles for miRNA delivery in H. pylori- and EBV-related carcinogenesis.
Highlights
Specialty section: This article was submitted to Infectious Diseases, a section of the journal Frontiers in Microbiology
This review focuses on the role of (1) infectious agents, (2) non-coding RNAs, mainly microRNAs and long ncRNAs, and extracellular vesicles, (3) exosomes and (4) vesicles of bacterial origin; in the gastric precancerous cascade
A study by Sato et al (2017) provides a hint toward the mechanism explaining this controversial observation. They demonstrated that co-culture of latent membrane protein 1 (LMP1)-positive and negative gastric cancer cells leads to elimination of LMP1positive cells, through the release of LMP1-loaded exosomes that mediate epidermal growth factor receptor (EGFR) activation in LMP1-negative cells
Summary
Gastric cancer (GC) is one of the most common cancers worldwide (Ferlay et al, 2015). In the case of the intestinal-type GC, a long-standing preneoplastic process known as the “Correa cascade” begins with multifocal atrophic gastritis, progressing to intestinal metaplasia and cancer over the 30– 50 years (Carrasco and Corvalan, 2013; Sandoval-Bórquez et al, 2015). Infectious agents such as Helicobacter pylori (H. pylori) and Epstein-Barr virus (EBV), as well as host-dependent genetic [polymorphisms in interleukin (IL)-1β, TNF-γ, and IL-10] and environmental factors (i.e., smoking and alcohol consumption), play roles in the heterogeneity of this preneoplastic cascade (Figure 1). This review focuses on the role of (1) infectious agents, (2) non-coding RNAs (ncRNAs), mainly microRNAs (miRNAs) and long ncRNAs (lncRNAs), and extracellular vesicles, (3) exosomes and (4) vesicles of bacterial origin; in the gastric precancerous cascade
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