From infection to invasion: The role of deleted in malignant brain tumors 1 in Helicobacter pylori-driven gastric cancer

Abstract

Gastric cancer (GC) remains a major health challenge worldwide, with Helicobacter pylori (H. pylori) infection playing a key role in its development. H. pylori creates a mutagenic environment in the stomach by causing chronic inflammation, oxidative DNA damage, inducing DNA double-strand breaks, and disrupting DNA repair mechanisms and cell cycle checkpoints. Cytotoxin-associated gene A is the main carcinogenic component of H. pylori and interacts with signaling pathways to promote carcinogenesis. Deleted in malignant brain tumors 1 (DMBT1), a potential tumor suppressor gene, shows variable expression patterns in GC. DMBT1 is frequently downregulated in well-differentiated gastric adenocarcinomas but upregulated in other GC types. The correlation between DMBT1 expression and H. pylori infection is important, as maintained DMBT1 expression in precancerous states may protect against gastric carcinogenesis, while its downregulation may facilitate tumor progression. DMBT1 functions as a pattern recognition receptor that binds to H. pylori and other pathogens and modulates inflammatory and immune responses. H. pylori colonization of gastric mucosa can induce an inflammatory microenvironment, which influences tumor suppressor gene expression, including DMBT1. Understanding the interactions between DMBT1 and H. pylori may reveal new therapeutic targets and preventive strategies for H. pylori-associated gastric disease.

Key Words: Gastric cancer; Deleted in malignant brain tumors 1 expression; Helicobacter pylori; Carcinogenesis; Infection

Core Tip: Gastric cancer (GC) remains a major global health issue closely linked to Helicobacter pylori (H. pylori) infection, which induces chronic inflammation, oxidative DNA damage, and disrupts cell cycle regulation. Cytotoxin-associated gene A plays a significant role in carcinogenesis. Deleted in malignant brain tumors 1 (DMBT1), a potential tumor suppressor, shows variable expression in GC, often being downregulated in well-differentiated adenocarcinomas and upregulated in other subtypes. DMBT1 interacts directly with H. pylori to modulate the immune response. Preserved DMBT1 expression may protect against gastric carcinogenesis, whereas its downregulation may facilitate tumor progression. Understanding the DMBT1-H. pylori interaction could help identify new therapeutic strategies for the prevention and treatment of GC.

INTRODUCTION

Gastric cancer (GC) continues to be a major health challenge worldwide, although its incidence is declining in many areas[1]. In 2017, more than 1.22 million new cases of GC were reported globally, leading to 865000 fatalities and 19.1 million Disability Adjusted Life Years[2]. East Asian countries, such as China, Japan, and Korea, account for nearly 50% of these cases[1]. Extensive screening and early detection programs in Japan and South Korea have enhanced early diagnosis rates, leading to improved outcomes[3]. However, in most regions, GC is frequently diagnosed at advanced stages owing to nonspecific symptoms and a lack of screening, leading to poor survival rates. Although the overall 5-year survival rate for GC has improved slightly over the past decade, it remains approximately 10%-30% in European countries[4]. In United States, the 5-year relative survival rate is 36.4% for all stages combined, increasing to 75.4% if detected early but dropping to no more than 7.0% in metastatic cases[5]. In this scenario, Helicobacter pylori (H. pylori) is recognized by the World Health Organization as a class I carcinogen for GC and plays a pivotal role in its etiology[6]. Understanding how chronic H. pylori infection drives gastric carcinogenesis and identifying the key molecular players in this process are crucial for developing new interventions. One such player is deleted in malignant brain tumors 1 (DMBT1), a protein-coding gene[7]. Zhou et al[8] published the study in the latest issue. Zhou et al[8] examined the effects of H. pylori infection and the silencing of the DMBT1 gene on human gastric carcinoma cell cultures. The authors discovered that H. pylori positivity and DMBT1 negativity had an additive effect of on cell proliferation, invasion, and metastasis[8]. This article explores into the pathway “from infection to invasion”, exploring epidemiological trends, H. pylori mutagenic mechanisms, core genetic pathways in gastric adenocarcinoma, and how H. pylori-induced alterations converge on DMBT1 downregulation to promote cancer progression.

METHODOLOGY

We reviewed the literature using the following search strategy in PubMed/MEDLINE database: ((gastric adenocarcinoma[Title/Abstract]) OR (gastric cancer[Title/Abstract])) AND (((personalized therapy[Title/Abstract]) OR (precision medicine[Title/Abstract])) OR (genetic therapy[Title/Abstract])) (Table 1). Additional scientific articles were retrieved from Nature Publishing database. Artificial intelligence softwares were used for contextual searching and English language editing[9].

Table 1 PubMed/MEDLINE search strategy.

Search number	Query	Results
6	((Gastric adenocarcinoma[Title/Abstract]) OR (gastric cancer[Title/Abstract])) AND (((personalized therapy[Title/Abstract]) OR (precision medicine[Title/Abstract])) OR (genetic therapy[Title/Abstract]))	347
5	((Personalized therapy[Title/Abstract]) OR (precision medicine[Title/Abstract])) OR (genetic therapy[Title/Abstract])	32605
4	gastric cancer personalized therapy	47189
3	((Gastric adenocarcinoma[Title/Abstract]) OR (gastric cancer[Title/Abstract])) AND ((Deleted in malignant brain tumors 1[Title/Abstract]) OR (DMBT1[Title/Abstract]))	16
2	(Deleted in malignant brain tumors 1[Title/Abstract]) OR (DMBT1[Title/Abstract])	338
1	(Gastric adenocarcinoma[Title/Abstract]) OR (gastric cancer[Title/Abstract])	92741

H. PYLORI AS A MUTAGENIC FACTOR IN GASTRIC CARCINOGENESIS

Approximately 40% of the world’s population harbors H. pylori in their stomach[10], which is typically acquired in childhood, and the bacterium can persist for life if left untreated[11]. In East Asian Countries, the seroprevalence is higher, with reported rates of 59.6%, 58.1%, 57%, 54.5%, and 39.3% in Korea, China, Thailand, Taiwan, and Japan, respectively[12].

Chronic infection with H. pylori, classified as a class 1 carcinogen[10], is a well-documented risk factor for gastric adenocarcinoma, with approximately 90% of GC cases attributed to this infection[13]. For those infected, there is a 5% lifetime chance of developing GC. H. pylori is the most common cancer-causing infectious agent, with GC representing 37% of all cancers linked to chronic infection[13].

H. pylori generated a mutagenic environment in the stomach by causing chronic inflammation, oxidative damage to DNA, thus inducing DNA double-strand breaks, and disrupting DNA repair mechanisms and cell cycle checkpoints[11].

Cytotoxin-associated gene A (CagA) is the main carcinogenic component of H. pylori and is found in almost all strains of this bacterium. There is a structural difference between East Asia-type CagA and Western-type CagA, with higher aggressivity for the former[14].

Intracellular insertion of CagA into the gastric mucosal cells interacts with partitioning-defective 1b, inhibiting partitioning-defective 1b-mediated breast cancer (BRCA) 1 gene, BRCA1 phosphorylation and decreasing the nuclear translocation of BRCA1[15]. The reactive oxygen species related to H. pylori infection also decreases BRCA activity. These effects include DNA double-strand breaks[16] and impairment of homologous recombination-mediated DNA repair[17].

CagA enhances the expression of squalene epoxidase, elevates cellular palmitoyl-CoA levels, stimulates programmed death-ligand 1 (PD-L1) palmitoylation, and reduces its ubiquitination[18]. Consequently, PD-L1 becomes more stable, T cell activity is suppressed, and immune evasion in GC is facilitated[18].

Ferroptosis is a type of cell death that relies on iron and is marked by the accumulation of lipid peroxides within cells and a disruption in reactive oxygen species balance, a process that H. pylori can influence as a carcinogenic mechanism[19]. The bacterial virulence factors that play a role in this include CagA, vacuolating cytotoxin A, neutrophil-activating protein A, superoxide dismutase B, gamma-glutamyl transpeptidase, lipopolysaccharide, and outer inflammatory protein A[19].

The H. pylori infection activates the protein kinase B/glycogen synthase kinase 3 beta (GSK3β) signaling pathway (Figure 1, adapted from[20-22]), with phosphorylation and inactivation of GSK3β, which promotes epithelial-to-mesenchymal transition, a process involved in the invasion and metastasis of cancer[6,23]. The H. pylori infection also creates epigenetic field defects, with epigenetic modifications of Wnt pathway-related genes, such as increased methylation of secreted frizzled-related protein 1 and dickkopf-related protein 1 host genes and secondary inhibition of Wnt signaling[24,25]. Both the phosphoinositide 3-kinases-protein kinase B and Wnt pathways converge to inactivate the kinase activity of GSK3β[26].

Figure 1 Molecular mechanisms of Helicobacter pylori involved in gastric carcinogenesis. Copyright for the image which was created by author in Biorender (https://BioRender.com/1oa1hc) (Supplementary material). H. pylori: Helicobacter pylori; AKT: Protein kinase B; APC: Adenomatous polyposis coli; ASPP2: Apoptosis-stimulating protein of p53 2; CagA: Cytotoxic-associated gene A; CD8+ T cell: Cytotoxic T lymphocyte; ERK: Extracellular signal-regulated kinase; GSK3: Glycogen synthase kinase 3; PD-L1: Programmed death ligand 1; SALSA: Salivary scavenger and agglutinin; SHP2: Src homology-2 domain-containing phosphatase Shp2; T4SS: Type IV secretion system.

Moreover, it has been established that H. pylori compromises the tumor suppressor protein p53, often referred to as the “guardian of the genome”[27]. H. pylori decreases the expression of the upstream transcription factor 1 transcription factor, which stabilizes p53 and consequently, genomic stability[27].

Pan et al[28] in a cluster randomized controlled trial conducted in Linqu County, China, analyzed 180284 eligible participants, from 980 villages, with a follow-up of 11.8 years[28]. The authors showed that successful H. pylori eradication, even in asymptomatic carriers, results in a reduction in GC incidence, with a hazard ratio of 0.81, 95% confidence interval: 0.69-0.96[28].

In patients with BRCA1 and BRCA2 pathogenic germline variants, when H. pylori infection is present[15] the risk of GC is three-fold higher, with a cumulative lifetime risk of 45.5% at 85 years of age, compared to 14.4% in carriers of BRCA mutations without H. pylori infection[29,30]. Usui et al[29] analyzed 1433 patients with GC and 5997 controls from a Japanese hospital and recommended H. pylori eradication when present in this subgroup of BRCA 1/2 positive patients[29,30].

Nonetheless, many individuals already infected for decades may have experienced irreversible molecular damage up to H. pylori eradication. Thus, understanding the precise mutational and epigenetic footprints of H. pylori is critical for the early detection and interception of gastric neoplasia.

DMBT1 AND GC

The DMBT1 gene is regarded as a potential tumor suppressor gene for cancers of the brain, lung, esophagus, stomach, and colorectum[31]. This is because of the frequent observation of homozygous deletions and the absence of mRNA expression in these types of cancer[31].

DMBT1 is located on chromosome 10q25.3-q26.1 and was originally identified as a deletion in brain tumors, including medulloblastomas and gliomas. DMBT1 encodes a glycoprotein that is classified as a scavenger receptor cysteine-rich protein, playing a role in various biological processes such as cellular differentiation, immune response, and epithelial protection[22,32]. Its role has expanded to include a range of malignancies, particularly those of epithelial origin, such as GC.

Previous studies have indicated that DMBT1 exhibits variable expression patterns in GC. Several studies have shown that DMBT1 is frequently downregulated in well-differentiated gastric adenocarcinomas but can be upregulated in other types of GC. For instance, Conde et al[33] found that DMBT1 was downregulated in 12.5% of patients with GC, but mentioned variability across different types of GC[33,34]. Garay et al[35] noted increased DMBT1 expression in precancerous gastric lesions associated with H. pylori infection, linking DMBT1’s expression to the pathogenic mechanisms of infection and GC progression[35].

The correlation between DMBT1 expression and H. pylori infection is particularly noteworthy, as the maintained expression levels of DMBT1 in precancerous states may serve as a protective mechanism against gastric carcinogenesis. In contrast, its downregulation may facilitate tumor progression, indicating a nuanced role for DMBT1 that could vary by cancer subtype and developmental stage[34,36]. The presence of H. pylori, a well-established gastric carcinogen, is associated with altered DMBT1 regulation, which affects both inflammatory and neoplastic outcomes[37].

Furthermore, additional research has proposed mechanisms by which DMBT1 is involved in GC through intracellular signaling pathways. Significantly, changes in the activity of protein kinases, including protein kinase C and extracellular signal-regulated kinases, have been recognized as factors influencing the expression of DMBT1 in gastric cells[38]. This underscores DMBT1’s potential role in mediating tumor-suppressive functions through various signaling cascades.

A recent meta-analysis has demonstrated a significant association between H. pylori infection and increased PD-L1 expression in GCs (odds ratio = 1.90, 95% confidence interval: 1.33-2.72, P < 0.001, I² = 53%), underscoring the connection between microbial factors and checkpoint molecule expression[39]. DMBT1 may counteract H. pylori-driven immunosuppressive signals by contributing to mucosal immune homeostasis. Preserved DMBT1 expression in H. pylori-positive gastric lesions has been hypothesized to limit carcinogenic progression by promoting immune clearance of the bacteria and infected cells[35,40]. Taken together, these insights point to the H. pylori and DMBT1 as potential modulators of the programmed death 1/PD-L1 axis in GC. In the era of immunotherapy, these effects are therapeutically relevant[41,42]. Shatila et al[43] reviewed retrospectively 2930 GC patients, of which 206 (7%) were treated with immunotherapy[43]. H. pylori infection was associated with worse 3-year overall survival in patients receiving immunotherapy (P = 0.041) but not in those who did not receive immune checkpoint inhibitors (P = 0.325)[43].

The implication of DMBT1 as a candidate tumor suppressor gene across multiple cancer types suggests that it may play a broader role in cancer biology. In addition to GCs, it has been shown to be typically downregulated or lost in breast, lung, and colorectal cancers[44,45]. The consistency of DMBT1 downregulation across various tumors of epithelial origin indicates its potential utility as a biomarker for identifying malignancies and assessing patient prognosis.

Despite these insights, the lack of uniformity in DMBT1 expression patterns across studies suggests the need for further investigation into its functional role in GC and overall carcinogenesis. Differences in the tumor microenvironment, genetic background, and disease stage may contribute to the variability in DMBT1 regulation[34]. Continued research is crucial to elucidate the mechanistic functions of DMBT1, its interactions with GC pathways, and its potential utility in clinical diagnosis and therapeutics.

INTERPLAY BETWEEN MALIGNANT BRAIN TUMOR 1 (DMBT1) AND H. PYLORI

The interaction between DMBT1 and H. pylori is important for understanding gastric pathology, especially in the context of gastric carcinogenesis. DMBT1 has been shown to be expressed at increased levels in precancerous gastric lesions, suggesting its potential involvement as a marker or mediator in GC progression linked to H. pylori infection[35,36,46]. Garay et al[35] proposed that DMBT1 interacts with trefoil factor 2 that is also modulated by H. pylori, indicating that both proteins may collaborate in the gastric mucosal response to bacterial infection. Moreover, the interaction of DMBT1 with H. pylori has been further elucidated, indicating that DMBT1 functions as a pattern recognition receptor that binds to H. pylori and various other pathogens through specific regions on DMBT1, particularly its scavenger receptor cysteine-rich domains[47,48]. The findings underscore the dual role of DMBT1, functioning not only as a receptor but also as a potential modulator of inflammatory and immune responses against H. pylori. This is particularly significant given that this bacterium is a well-established risk factor for GC[49,50].

Furthermore, H. pylori infection is commonly associated with gastritis and its complications. Studies have highlighted that the presence of H. pylori in the stomach lining can create an inflammatory environment, which may, in turn, influence the expression of tumor suppressor genes like DMBT1. For instance, Koopaie et al[36] noted that increased expression of DMBT1 in the context of advanced gastritis correlated with H. pylori infection[36], which is consistent with the findings of Mollenhauer and Poustka[46], which highlight the complex role of DMBT1 in gastric carcinogenesis.

Overall, these interactions suggest that DMBT1 is intertwined with dysregulated immune responses and oncogenic processes initiated by H. pylori in the gastric environment. The significant association between DMBT1 expression and H. pylori infection highlights its potential utility as a biomarker for monitoring the progression from gastritis to gastric neoplasia.

A similar mechanism was found for colonic dysplasia, in which DMBT1 glycoprotein is lost[51,52]. DMBT1 is highly upregulated by Clostridium difficile infection. The DMBT1 protein was downregulated in 100% of dysplastic foci in three murine models of colon tumorigenesis[52]. Green et al[52] suggested that DMBT1 is involved in the gut epithelial response to pathogens and acts as a key regulator of cell proliferation and differentiation during the healing process following injury. They tested this hypothesis using human organoids[52].

CONCLUSION

In conclusion, the interactions between DMBT1 and H. pylori are multifaceted, emphasizing DMBT1’s role as a player in the gastric mucosal immune response and its implications in GC pathology. Further elucidation of these interactions may provide insights into novel therapeutic targets and preventive strategies against H. pylori-associated gastric diseases.