miR-136: A biomarker in the inflammation-cancer transformation of gastric cancer

Abstract

The study by Chen et al found that miR-136 plays an indispensable role in the inflammation-cancer transformation in gastric cancer (GC). The authors conducted in vivo and in vitro experiments and verified them in conjunction with functional and molecular mechanisms. Their key findings indicate that Helicobacter pylori (H. pylori) activated NF-κB/miR-136/PDCD11 axis to induce the growth of H. pylori-positive GC tumors. And miR-136 is markedly associated with characteristics related to the gastric mucosal histopathological, supporting its use as a diagnostic biomarker and a therapeutic target for early H. pylori-induced GC. Chronic inflammation is one of the important precancerous lesions. With the development of emerging technologies such as multi-omics technology, the pathways linking chronic inflammation to cancer have been extensively elucidated. In this letter, we focus on introducing the molecular mechanisms of chronic inflammation in the development of GC, which will provide new insights for early diagnosis, personalized treatment, and prognosis assessment of GC.

Key Words: Gastric cancer; Helicobacter pylori; Inflammation; miR-136; NF-κB; Signaling pathway; Cell death; Immune infiltration

Core Tip: Helicobacter pylori (H. pylori)-induced inflammation plays a crucial role in the development of gastric cancer (GC). A comprehensive understanding of the molecular mechanisms driven by H. pylori infection in the development of GC is essential for the timely diagnosis of tumors and the formulation of corresponding personalized treatment strategies. Reviewing the mechanisms of inflammation-cancer transformation induced by H. pylori infection in GC, will help in identifying potential patient stratification factors and formulating personalized treatment strategies for GC patients.

INTRODUCTION

Gastric cancer (GC) is the fifth most common cancer in terms of incidence and mortality according to the GLOBOCAN database in 2022, with nearly one million new cases reported each year[1]. Helicobacter pylori (H. pylori) infection, diet, obesity, smoking, and genetic susceptibility are all risk factors for GC, among which H. pylori infection (75% attributable risk) is the main risk factor. Over 95% of GC patients have a history of H. pylori infection[2-4]. After H. pylori infection, normal gastric mucosa develops into GC through a series of histological changes, with the first stage being chronic gastritis[5]. Therefore, the discovery of new biomarkers related to H. pylori infection will help guide the diagnosis and treatment of GC. Previous studies have shown the complexity of miR-136 in the development of GC[6-8]. A recent study by Chen et al[9] revealed that miR-136 promotes the proliferation and migration of H. pylori-positive GC cells through the NF-κB/miR-136/PDCD11 pathway. Specifically, compared with non-active gastritis and chronic atrophic gastritis (CAG), miR-136 exhibits significantly differential expression in precancerous lesions of GC (PLGC). In Operationally Defined Staging Criteria for Gastritis (OLGA)/Operative Link for Gastritis Intestinal Metaplasia (OLGIM) III-IV cases, which are associated with GC progression, the expression of miR-136 can also stratify high-risk CAG and PLGC.

H. pylori colonization of the gastric mucosa is an established risk factor for gastritis, peptic ulcers, and GC[10]. The Correa cascade model indicates that after H. pylori infection, normal gastric mucosa goes through a process of chronic gastritis, gastric atrophy, intestinal metaplasia, and dysplasia, eventually developing into GC[11]. The virulence factors released after H. pylori infection can promote inflammation-cancer transformation not only by directly contacting and activating signaling pathways in GC cells but also by inducing immune responses and releasing pro-inflammatory cytokines and chemokines. Although current treatment strategies have achieved some success, many patients still cannot benefit from them. A comprehensive reorganization of the molecular mechanisms mediating GC development driven by H. pylori infection will contribute to overcoming the dilemma. Therefore, in this letter, we briefly review the research on the inflammation-cancer transformation of GC to enhance our understanding of the role of H. pylori infection in driving GC development.

THE SIGNALING PATHWAYS IN THE INFLAMMATION-CANCER TRANSFORMATION OF GC

The study by Chen et al[9] revealed that the NF-κB pathway plays a key role in the upregulation of miR-136 to accelerate the progression of H. pylori infection to GC. Extensive research results also indicate that signaling pathways such as STAT3, Wnt/β-catenin, cGAS-STING, MAPK, PI3K/AKT/mTOR, Hippo, Sonic Hedgehog, and TGF-β1 are all involved in this process[12-15]. Apparently, the dysfunction of so many pathways reflects that the carcinogenic effect of H. pylori infection cannot be attributed to a single signaling pathway, but rather the result of cascading regulation caused by crosstalk among multiple signaling pathways. These research results indicate that the virulence factor CagA plays a central role in the process of inflammation-cancer transformation after H. pylori infection. On the one hand, it directly activates the inflammatory response through the NF-κB pathway, secreting pro-inflammatory cytokines and regulating the infiltration of immune cells; on the other hand, it accelerates the carcinogenic effect by directly or indirectly regulating signaling pathways such as PI3K/AKT, Wnt/β-catenin, and Hippo[16-18]. Additionally, CagA can amplify the carcinogenic signal transmission through the crosstalk of NF-κB and other signaling pathways[19-21]. Therefore, considering that H. pylori infection promotes GC through the multifaceted action of NF-κB, further clarification of the regulatory role of NF-κB on the signaling pathway network in the inflammation-cancer transformation of GC is required.

THE PROGRAMMED CELL DEATH IN THE INFLAMMATION-CANCER TRANSFORMATION OF GC

H. pylori infection-induced gastric damage greatly promotes the inflammation-cancer transformation of GC. While existing research indicates that apoptosis is the primary form of cell death involved in the H. pylori infection process, but necroptosis, pyroptosis, and ferroptosis also participate[22]. Studies have found that the apoptosis induced by H. pylori infection is also diverse. Gastric T cells promote epithelial cell apoptosis through interaction with Fas/FasL[23]. H. pylori infection induces miR-223 upregulation, which then regulates the cell cycle and apoptosis of GC cells by targeting FBXW7[24]. Acute H. pylori infection can also induce gastric epithelial cell apoptosis by upregulating the expression of BAX and cutting down the expression of caspase-3, as well as downregulating BCL-2[25]. In addition to epithelial cells, H. pylori infection can also induce apoptosis in immune cells. Singh et al[26] found that the apoptosis of T cells and B cells in H. pylori-infected cells significantly increased. Furthermore, various myeloid cells have been reported to undergo apoptosis as well[27,28]. Ferroptosis, as a form of cell death caused by iron-dependent lipid peroxidation[29], has also been reported in H. pylori infection. Similar to its double-edged sword effect in other tumors[30,31]. After H. pylori infection, ferroptosis is beneficial to the formation of an inflammatory environment and promotes immune cell death[32,33], while H. pylori infection can also inhibit ferroptosis to promote the progression of GC[34-38]. RIPK3 is one of the key mediators of necroptosis[39], and the positivity of RIPK3 in gastric biopsy and atrophy samples infected with H. pylori significantly increased[40], but the key mechanisms remain unclear. There is also a lack of research on pyroptosis induced by H. pylori infection, but various virulence factors (UreB, CagA, FlaA, and VacA, etc.) have been reported to regulate cell pyroptosis, thereby activating an inflammatory cascade response[41,42]. Clarifying the sensitivity of various programmed cell deaths in inflammation-cancer transformation process after H. pylori infection will not only help understand the pathogenesis of GC induced by H. pylori but will also contribute to the development of more personalized treatment strategies for patients based on their sensitivity.

THE IMMUNE INFILTRATION IN THE INFLAMMATION-CANCER TRANSFORMATION OF GC

Previous research has shown that H. pylori infection leads to the infiltration of a large number of inflammatory cells, including tumor-associated macrophages (TAMs), neutrophils, dendritic cells (DCs), myeloid-derived suppressor cells, and natural killer cells[43]. With the advancement of sequencing technology, single-cell RNA sequencing (scRNA-seq) has become a powerful tool for assessing gene expression at the single-cell level and has recently been used to analyze the cell diversity and microenvironment heterogeneity in the GC microenvironment. Li et al[44] found that in the process of gastritis, gastrointestinal metaplasia, and GC, the proportion of epithelial cells gradually decreased, while myeloid cells increased accordingly. This emphasizes the dynamic changes occurring in the tumor microenvironment. Another study using metagenomics and scRNA-seq also found that H. pylori infection severely alters the composition and functional characteristics of the gastric microbiota. In addition, in individuals infected with H. pylori, there was an expansion of CD11c⁺ myeloid cells and activated CD4⁺ T cells and B cells, with B cells acquiring an activated phenotype[45]. Chen et al[46] used RNA-seq data from GC and H. pylori-infected GC patients to evaluate the immune cell infiltration status, showing that the number of DCs and T cells were significantly increased in H. pylori infection samples. Studies in mouse models have shown that concurrent H. pylori infection and metaplasia driven by constitutive active KRAS induce tissue changes, accompanied by the emergence of features of epithelial-to-mesenchymal transition (EMT) and an increase in the proportion of Muc4⁺ Pit cells caused by inflammation[47]. IL11⁺ inflammatory CAFs, VEGFA⁺ angiogenic TAMs, TREM2⁺ TAM, and suppressive T cells were also significantly enriched in H. pylori-infected GC samples, and it was proposed that the expression of NECTIN2 in the immune and stromal components induced by H. pylori infection is a potential target for immune evasion in GC cells[48]. In general, existing research indicates that the regulatory role of H. pylori infection on immune cell infiltration is complex, and the source or quantity of samples may be one of the significant limitations. The cell populations differing in single-cell results among different research groups are not entirely consistent, but they generally exhibit EMT characteristics. Further work is needed to fully reveal the single-cell landscape from chronic inflammation to GC stages following H. pylori infection.

CONCLUSION

In summary, the results by Chen et al[9] highlight the potential application value of constructing a predictive model based on the expression level of miR-136 and OLGA/OLGIM staging for the diagnosis of H. pylori-positive GC. In this letter, we summarize the main signaling pathways in the inflammatory cancer transformation process of GC after H. pylori infection, as well as cell death and cell populations. A broader understanding of the crosstalk relationships between signaling pathways, particularly how NF-κB interacts with other signaling pathways, will contribute to revealing the comprehensive molecular landscape of the effects of H. pylori-induced GC. Moreover, there is a certain heterogeneity in the changes of cell populations involved in the inflammatory carcinogenesis process of GC across different studies, which may be due to the limitations of the study cohorts. Therefore, it is necessary to explore the changes in cell clusters during this process in large-scale multicenter cohorts, which will also be beneficial for discovering new immune cell types that can serve as GC biomarkers. Although H. pylori infection can promote the oncogenesis of GC, it has also been reported to increase the sensitivity of GC cells to ferroptosis. This finding suggests that activating ferroptosis may be a promising therapeutic strategy, and focusing on delineating the genetic basis of this sensitivity will be one of the important research directions in the future. A comprehensive understanding of the molecular mechanisms in inflammation-cancer transformation, and advancing prognostic factors/immune cells and other GC biomarkers, can enable more accurate early diagnosis for patients with gastritis and provide more personalized precision treatment plans for patients with GC.