Abstracting and Indexing

  • Google Scholar
  • Semantic Scholar
  • CrossRef
  • WorldCat
  • ResearchGate
  • Academia.edu
  • Scilit
  • Baidu Scholar
  • DRJI
  • Microsoft Academic
  • Academic Keys
  • Academia.edu
  • OpenAIRE

Roles of Helicobacter pylori in the Epithelial-Mesenchymal Transition of Gastric Cancer

Article Information

Shuai Ruan1#, Wenjie Huang1#, Fang Wen1, Xiaona Lu1, Su Ping Gu1, Xiao Xue Chen1, Miao Liu2*, Peng Shu3*

1First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China

2Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Massachusetts, USA

3Oncology Department, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China

*Corresponding author: Miao Liu, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Massachusetts, USA

Peng Shu, Oncology Department, Jiangsu Province Hospital of Traditional Chinese Medicine, 155 Hanzhong Road, Nanjing, Jiangsu province, China

#Authors contributed equally to this article

Received: 12 June 2020; Accepted: 01 July 2020; Published: 13 July 2020

Citation: Shuai Ruan, Wenjie Huang, Fang Wen, Xiaona Lu, Su Ping Gu, Xiao Xue Chen, Miao Liu, Peng Shu. Roles of Helicobacter pylori in the Epithelial-Mesenchymal Transition of Gastric Cancer. Archives of Clinical and Biomedical Research 4 (2020): 254-267.

View / Download Pdf Share at Facebook

Abstract

Gastric cancer (GC) is one of the most frequent malignant tumors in humans, with over 50% of patients after treatment suffering from recurrence and peritoneal metastasis. Helicobacter pylori (H. pylori) infection is critical to the development of GC. The phenomenon of epithelial-mesenchymal transition (EMT) in GC is linked with development of the invasive phenotype, which is very likely regulated by H. pylori through altering signaling pathways in the gastric cells. In this review, we conclude the current studies on how H. pylori affects the EMT of GC, thus contributing to its initiation and metastasis.

Keywords

Helicobacter pylori; Epithelial-mesenchymal transition; Gastric cancer; cag pathogenicity island (cag PAI); Cytotoxin-associated gene A antigen (CagA); TNF-α-inducing protein (Tipα); matrix metalloproteinases (MMPs); tumor microenvironment (TME)

Helicobacter pylori; Epithelial-mesenchymal transition; Gastric cancer; cag pathogenicity island (cag PAI); Cytotoxin-associated gene A antigen (CagA); TNF-α-inducing protein (Tipα); matrix metalloproteinases (MMPs); tumor microenvironment (TME)

Article Details

1. Introduction

Gastric cancer (GC) is the fifth most commonly diagnosed malignancy and the third most common cause of cancer-related death worldwide [1, 2]. Over 70% of GC cases occur in developing countries with half the global total cases occurring in Eastern Asia [3]. On the basis of compelling evidence, the World Health Organization (WHO) has confirmed that the incidence of GC, particularly gastric adenocarcinoma (GAC), is closely related to the presence of a class I carcinogen, namely, Helicobacter pylori (H. pylori) [4, 5]. Since Marshall and Warren first identified H. pylori in 1983, a diverse spectrum of gastrointestinal diseases has been found to link with this causative agent, including gastric and duodenal ulceration, GAC, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric non-Hodgkin’s lymphoma [6]. On the basis of regional prevalence estimates, approximately 4.4 billion individuals were infected with H. pylori globally in 2015. That is, H. pylori affected more than half the world's population [7]. Among the patients with H. pylori, approximately 10% ends up with peptic ulcer disease, 1-3% develops GC, and 0.1% suffers from gastric MALT lymphoma [8]. Due to unsuccessful eradication-related reinfection and recidivation, intrafamilial transmission associated with low socioeconomic status (e.g., more crowded living conditions) or iatrogenic infection by means of endoscopes, the amount of H. pylori infected population has persisted or even increased over the past three decades throughout the world [9].

Metastasis is the main cause of death for GC patients, with over 50% of patients suffering from recurrence and peritoneal metastasis after treatment [10]. The major mechanism of metastasis is the epithelial-mesenchymal transition (EMT) [11]. EMT is a developmental process during which epithelial cells acquire the properties of motility and migration like mesenchymal cells. EMT is relevent to the development of invasive phenotype of GAC [12]. Evidences also suggest that cells undergoing EMT obtain stem cell-like characteristics [13]. EMT-induced cancer stem cell phenotype is conductive to the initiation of GC [14]. Recent studies have indicated that H. pylori promotes EMT in gastric cancer [11, 15]. For example, eradication of H. pylori reduces the expression of TGF-β1 and increases E-cadherin expression. This indicates that H. pylori is a trigger of TGF-β1-induced EMT [16]. Lee et al. pointed that cytotoxin-associated gene A (CagA), the major virulence factor of H. pylori, leads to Snail-mediated EMT by reducing GSK-3 activity [17]. Besse`de et al. also demonstrated that H. pylori induces the EMT-like variations in gastric epithelial cells, which unveil CSC-like properties [18]. Hence, it is critical to understand the molecular mechanisms of H. pylori-induced EMT in order to develop new strategies against GC.

In this review, we will illustrate epidemiology of H. pylori-related gastric malignancies, discuss the factors influencing the EMT of GC, and elaborate on recent developments in the molecular mechanisms of H. pylori-induced EMT in GC.

2. Epidemiology of H. pylori-related gastric malignancies

1. pylori is micro-aerophilic Gram-negative bacillus which is spiral-shaped and flagellated. This kind of bacillus colonizes the gastric mucosa of more than 50% of human beings, while developing countries have the highest prevalence [19]. As a class I carcinogen, H. pylori is a causative factor in the cascade leading to GAC, especially non-proximal cancers [8, 9]. A recent large retrospective cohort research, including 371,813 patients in the US with a diagnosis of H. pylori infection, found that the cumulative incidence rate of GC at 5, 10, and 20 years after detection of infection was 0.37%, 0.5%, and 0.65%, respectively [4]. This study also showed that treatment of H. pylori infection hardly reduce the risk of GC unless eradication of H. pylori [4]. Analogously, a systematic review and meta-analysis of six randomised controlled trials (RCTs) suggested that searching for and eradicating H. pylori infection were useful tools in reducing the subsequent incidence rate of GC in healthy asymptomatic infected Asian individuals, with a pooled relative risk of 0.66 (95% CI: 0.46-0.95) [20]. This data is confirmed by a meta-analysis by Lee et al. in 2016. They reported that after H. pylori eradication, GC risk was decreased by about 35% [21]. Yet, studies also show that infection alone is not adequet for carcinogenesis, proved by high H. pylori prevalence and low GAC occurance in sub-Saharan Africa (the “African enigma”), or different incidence rates of GAC throughout Middle Eastern countries despite high H. pylori burden [7, 22].

3. Factors affecting the EMT of GC

EMT is produced by complex molecular and cellular procedures, through which the epithelial cells dedifferentiate, loose intercellular adhesion and apical-basal polarity, and acquire mesenchymal characteristics, including motility, invasiveness, and a heightened resistance to apoptosis. Theoretically, epithelial cells obtain the phenotype of mesenchymal cells, such as fibroblasts, which is the generation of EMT [23]. EMT is crucial in the tumorigenic process, contributing to invasion, motility, and a heightened resistance to apoptosis. Abnormal biological behaviors in the EMT of adult epithelial cells inhibit cell adhesion molecules, resulting in a decrease in cell adhesion ability, thereby allowing tumor cells to spread in the body and ultimately promoting tumor metastasis [24]. Therefore, EMT is considered as the beginning of invasion and metastasis, and it also indicates that the tumor cells have a strong ability of invasion and metastasis. In the process of EMT, the cells shut down the expression of epithelial biomarks, like cytokeratins and E-cadherin, and lead to the expression of mesenchymal markers, including vimentin, fibronectin, N-cadherin and integrin, and the expression of other regulatory molecules like SNAIL, TWIST and SLUG, which change obviously [25-27]. Oncogenic pathways inducing EMT include transforming growth factor β (TGF-β), Src, Ets, Ras, Wnt/β-catenin, Notch, nuclear factor-κB and integrin [28-30].

Many factors influence the EMT in GC. One of the classic oxidative stress-related malignances is GC [31], indicating that certain redox-sensitive factors may be important EMT modulators. Taking SENP3 as an example, it is a redox-sensitive SUMO2/3-specific protease. SENP3 induces and promotes the EMT of GC cells by de-conjugating SUMO2/3 and activating an EMT-inducing transcription factor called FOXC2 [32]. Hypoxia causes the decrease of E-cadherin, and leads to the increase of N-cadherin, Vimentin, Snail, Sox2, Oct4, and Bmi1, In other words, the hypoxic microenvironment facilitates the generation of EMT, together with cytoskeleton remodeling [33]. Cytokines, chemokines and matrix metalloproteinases (MMPs) are the inflammatory mediators which also participate in the EMT of GC [11]. All constituents of the tumor microenvironment can secrete cytokines, such as TNF-α, IL-8, TGF-β, TGF-α, and IL-6, which seem to change the EMT of GC cells [34]. CXCR4 and CCR7 are the most important two chemokine receptors in GC. Actin polymerization is activated after CXCR4 binding its ligand CXCL12, inducing cell motility and the EMT [35-37]. Activation of CCR7 signaling leads to the initiation of EMT in GC cells, by transforming the expression of E-cadherin, MMP-9, and Snail. Thus, cells metastasize toward lymph vessels successfully [38, 39]. The MMP family degradates the extracellular matrix (ECM) and basement membrane barriers, for which this family becomes one of the most important inducers of the EMT [40]. Recent studies have also suggested some other mechanisms for inducing GC EMT. Erythropoietin-producing hepatocellular A2 (EphA2) upregulation, a common event in GC, promotes EMT through activation of Wnt/β-catenin signaling [41]. In human GC tissues, when Aquaporin 3 (AQP3) is overexpressed, which will promote the induction of EMT via the PI3K/AKT/Snail signaling pathway [42].

Recently, researchers found that coculturing H. pylori with gastric epithelial cell lines (AGS, MGLVA1, and ST16) contributed to the upregulation of the expression of EMT-associated genes like Snail, Slug, and vimentin [12]. It is reported that treating the human gastric cancer cells with H. pylori induces cytoskeletal reorganization through activation of Rac [43] and phosphorylation of focal adhesion kinase (FAK) [44]. As a result, H. pylori infection seems to act as an inducer of cell adhesion and motility. Thus, H. pylori infection may induce or facilitate EMT process in the GC microenvironment [45].

4. Molecular Mechanisms involved in the EMT of H. pylori-related GC

pylori is related to the development of gastric adenocarcinoma and lymphoma. H. pylori metastasizes to host cells, thereby regulating cell proliferation, affecting the normal apoptotic pathway, influencing cell shape, eliminating connection activity, and promoting EMT phenotype [46, 47]. In the environment of gastric cancer, the bacterial virulence factors involved include cytotoxin-related gene A antigen (CagA), vacuolar cytotoxin (VacA) and outer membrane protein (OMP) [48]. In the following, we will summarize the key mechanisms through which H. pylori induces the EMT of GC.

4.1 cag PAI

The virulence of H. pylori is closely related to the cag pathogenic island (cag PAI) locus encoding the type IV secretion system (T4SS) and the bacterial oncoprotein CagA [49]. The cag pathogenic island of the pathogenic H. pylori type I strain, with a genetic element of approximately 40 kb, encodes a type IV secretion system for exporting virulence determinant. What’s more, virulence determinants is closely related to gastric malignant progression [51]. The T4SS forms a syringe-like fimbria structure through which CagA can be injected into target cells [8]. H. pylori containing cag PaI increases the expression of matrix metallopeptidase 7 (MMP-7) by up-regulating gastrin secretion via activating gastrin releasing peptide (through the T4SS), leading to increased levels of soluble heparin-binding epidermal growth factor (HB-EGF), thereby triggering the expression of key EMT proteins (e.g., Snail, Slug and Vimentin), which may eventually play a role in the GC development [12].

4.2 CagA protein

A major virulence factor for H. pylori is the cytotoxin-related gene a (CagA), which encodes the cagA protein in cag PAI. CagA deliveres into gastric epithelial cells via the T4SS and results in cellular transformation [52, 53]. Injecting CagA into gastric epithelial cells induces EMT, which might be the critical triggers of carcinogenesis [54]. CagA+ H. pylori infection of normal human gastric epithelial cells increases the expression of EMT symbols Slug and Snail, thus increasing invasion and migration [55]. CagA induces epithelial cells to transition from a polarized state to an invasive phenotype, which is the cellular characteristic of EMT, depending on the signaling triggered by the CagA C-terminal EPIYA motif and the N-terminal mediated CagA localization in the intercellular junction [56]. Whole-genome expression arrays reveal that the intracellularly translocated CagA regulates the expression of EMT-related genes, regardless of the phosphorylation status of CagA [57]. H. pylori CagA, as a pathogenic scaffold protein, binds GSK-3 in a similar manner to Axin to make it insoluble, resulting in reduced GSK-3 activity, thereby stabilizing E-cadherin transcription repressor Snail which finally induces the EMT of GC [17]. H. pylori CagA, acting as a pathogenic protein, promotes oncogenic YAP pathway, which leads to EMT and gastric cancer [58]. In addition, H. pylori CagA can induce gastric cancer cells to produce TWIST1 or vimentin, and inhibit the expression of epithelial cadherin. CagA-induced EMT partly depends on PDCD4 regulation. TWIST1 and PDCD4 are involved in EMT of GC [59]. Studies have showed that microRNAs (miRNAs) play a key role in  GC associated with H. pylori [60, 61]. Compared with H. pylori-negative cancer tissue samples, miRNA microarrays display that miR-543 expression was remarkably increased in H. pylori-positive gastric cancer tissue [62]. Shi et al. reported that in GC which associated with H. pylori, the overexpression of miR-543 is induced by CagA, causing the translational repression of SIRT1 and suppressing autophagy. Subsequently cell migration and invasion are caused by increased expression of EMT [63]. CagA- and penicillin-binding protein 1A (PBP1A) mutation-positive H. pylori (CagA+/P+) strain promotes EMT in GC via the suppression of microRNA-134 [64].

pylori CagA also influences the cells surrounding GC, mainly activated cancer-associated fibroblasts (CAFs), which create molecular microenvironment promoting tumorigenesis and cancer invasion [65, 66]. H. pylori CagA can induce the activation and differentiation of gastric fibroblasts, mediated by transcription factors NFκB and STAT3 signaling leading to rapid Snail1 protein expression, which may finally activate the secretome responsible for fibroblasts inflammatory and EMT-inducing microenvironment serving for GC development [10]. Normal fibroblasts which induced by H. pylori (cagA+vacA+) strain were differentiated into CAFs, which may initiate the EMT process in normal RGM?1 epithelial cell line [67]. Jin et al. also found that H. pylori (cagA+vacA+) upregulates the transcription of ZEB together with expression of claudin-2 and CDX-2, by this way the EMT of AGS cells is promoted [68].

4.3 Tipα

pylori in the gastric epithelium releases a carcinogenic factor called the tumor necrosis factor-α (TNF-α)-inducing protein (Tipα) [69], resulting in induction of EMT in human gastric cancer cell lines [70]. Tipα protein composes of 172 amino acids with 19 kDa and plays a role of homodimer with 38 kDa, which is one of the strong TNF-α inducers [70]. Large amounts of Tipα can be secreted by H. pylori isolated from gastric cancer patients. Tipα combines with gastric cancer cells by directly binding to nucleolin on the cell surface, during which nucleolin is the receptor of Tipa [70-72]. Tipα is shuttled from membrane to nuclei by surface nucleolin [71], leading to the expression of TNF-α gene through activating NF-κB [69], inducing the process of EMT [73]. Researchers reported that Tipα resulted in formation of filopodia in gastric cancer cell lines, suggesting invasive morphological changes and reducing the Young's modulus of gastric cancer cells, the latter represented that cell stiffness falls and cell motility increases [70]. In human gastric cancer cells, the morphological changes induced by Tipα are crucial phenotypesc of EMT. In terms of molecular mechanisms, Tipα enhances phosphorylation of cancer-related proteins, and increases the expression of vimentin (a significant marker of EMT) with activation of MEK-ERK1/2 signal cascade [70]. Tipα also accelerates tumor aggressiveness in GC by promoting EMT through the way of activating IL-6/STAT3 signaling pathway [74].

The protein Lpp20 (hp1456) is one of the key 344 genes contributing to H.pylori survival and host colonization [75] locating in the cell envelope or being released inside membrane vesicles in the culture medium [76], is a structural homologue of Tipα and promotes EMT of H.pylori [77]. It is proved by researchers that in vitro, Lpp20 induces the down-regulation of E-cadherin in gastric cancer cells, besides promotes the migration and proliferation of cells together with the formation of filopodia [77].

4.4 MMPs

pylori infection upregulates the expression of matrix metalloproteinase (MMP) family for the reason that the proteins needed to be secreted by pathogens to help their adherence to epithelial gastric cells [78, 79]. The MMPs are one of the most important inducers of the EMT, which induces the EMT by means of  the degradation of the extracellular matrix (ECM) and decompose basement membrane barriers [40]. Researchers found that the invasion ability of gastric cancer cells is enhanced by increased expression of MMP-2 and MMP-9, which assioated with the metastasis of GC [80-82]. Upregulation of MMP-7 expression is a biological marker of H. pylori-associated GC, potentially regulating the progression of GC through the EMT [12, 83, 84].

4.5 TME

Tumor cells and stroma, a network of blood vessels and a variety of infiltrating inflammatory cells consitituted the tumor microenvironment (TME). These cells significantly promote the progression of GC [85, 86]. H. pylori infection mainly targets on gastric fibroblasts and promotes to the paracrine interactions between H. pylori, gastric fibroblasts, and epithelial cells. Gastric fibroblasts activated by H. pylori can secrete TGF-β, which prompting their differentiation toward CAF-like phenotype and the EMT-related phenotypic shifts in normal gastric epithelial cell populations, which is the prerequisite for GC development [87]. H. pylori-infected fibroblasts show enhanced expression of Snail1 and Twist mRNA[88]. Twist1 is a key regulator of EMT in the GC microenvironment, making an influence on transisting normal fibroblasts (NFs) to CAFs with CXCL2 which acts as the target for transcription [89]. Infected with H.pylori in GC may induce a signaling pathway which is called cyclooxygenase-2/prostaglandin E2(COX-2/PGE2) [90]. In CAFs the hyper-methylation of miR-149 is induced by PGE2, contributing to the enhanced secretion of IL-6 [91], which may induce EMT through activating the JAK2/STAT3 pathway in GC [92]. Mesenchymal stem cells (MSCs), which have multipotent differentiation potential. At the sites of cancer and inflammation, MSCs shows its tropism [93, 94]. MSCs are key components of the H. pylori infection-associated GC microenvironment, which may be of big importance for GC cell migration [45]. H. pylori-infected MSCs obtain the pro-inflammatory phenotype by secreting a combination of multiple cytokines, which are NF-κB-dependent and enhancing the migration of GC cells by promoting EMT [45].

4.6 Other signalings

An actin-binding protein called Afadin is associated with nectins at adherens junctions meanwhile  connected with ZO-1 instantly, and regulates the formation and stabilization of the junctional complexes [95, 96]. The expression of Afadin is downregulated when H. pylori infection happens, resulting in the emergence of EMT and the acquisition of an aggressive phenotype of gastric cells. This may contribute to the occurrence of GC [97]. Zhou et al. reported that infection with H. pylori  promotes EMT of gastric cells by upregulating lysosomal-associated protein transmembrane 4β (LAPTM4B) [98]. H. pylori infection triggeres the EMT pathway which is induced by TGF-β1, and causes the appearance of gastric cancer stem cells, for example, CD44v8-10 [99]. Meanwhile, Chang et al. points out that the EMT pathway which is induced by TGF-β1only upregulates the TGF-β1when cagE-positive H. pylori infection occurs,thereby promoting EMT [100]. A protein specifically localized in the Golgi apparatus called PAQR3, is markedly down-regulated in human GC, and is related to H. pylori infection negatively. PAQR3 expression level is tightly in relation to the progression and metastasis of GC [101]. H. pylori infection is the cause of GC but host factors are also implicated. IQGAP1 is a scaffolding protein of the adherens junctions interacting with E-cadherin and regulating cellular plasticity and proliferation, whose deficiency favours the acquisition of a mesenchymal phenotype and CSC-like properties induced by H. pylori infection [102].

5. Conclusions and Perspectives

In all types of cells, EMT phenomenon is closely related to tumor invasion and metastasis. This article focuses on the EMT process of gastric cancer. Due to infection with H. pylori, GC EMT is characterized by transient structural changes, loss of polarity, reduced contact with surrounding cells and matrix, enhanced cell migration, and altered cell phenotypes. This review demonstrates detailedly how H. pylori induces the EMT of GC through a variety of different mechanisms. Based on the key targets such as cag PAI, CagA, Tipα, MMPs, etc., we can develop strategies to inhibit gastric cancer metastasis. By blocking the factors that affect the occurrence of EMT and exploring new regulators, we are able to clarify the relationship between EMT and GC, and provide theoretical basis for the development of new drugs for GC invasion and metastasis.

References

  1. Arnold M, Park JY, Camargo MC, et al. Is gastric cancer becoming a rare disease? A global assessment of predicted incidence trends to 2035. Gut 69 (2020): 823-829.
  2. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68 (2018): 394-424.
  3. Fock KM and Ang TL. Epidemiology of Helicobacter pylori infection and gastric cancer in Asia. J Gastroenterol Hepatol 25 (2010): 479-486.
  4. Kumar S, Metz DC, Ellenberg S, et al. Risk Factors and Incidence of Gastric Cancer After Detection of Helicobacter pylori Infection: A Large Cohort Study. Gastroenterology 158 (2020): 527-536.
  5. Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 325 (1991): 1127-1131.
  6. Noto JM and Peek RM, Jr. Helicobacter pylori: an overview. Methods Mol Biol 921 (2012): 7-10.
  7. Hooi JKY, Lai WY, Ng WK, et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology 153 (2017): 420-429.
  8. Wang F, Meng W, Wang B, et al. Helicobacter pylori-induced gastric inflammation and gastric cancer. Cancer Lett 345 (2014): 196-202.
  9. Crowe SE. Helicobacter pylori Infection. N Engl J Med 380 (2019): 1158-1165.
  10. Krzysiek-Maczka G, Targosz A, Szczyrk U, et al. Involvement of epithelial-mesenchymal transition-inducing transcription factors in the mechanism of Helicobacter pylori-induced fibroblasts activation. J Physiol Pharmacol 70 (2019).
  11. Ma HY, Liu XZ, and Liang CM. Inflammatory microenvironment contributes to epithelial-mesenchymal transition in gastric cancer. World J Gastroenterol 22 (2016): 6619-6628.
  12. Yin Y, Grabowska AM, Clarke PA, et al. Helicobacter pylori potentiates epithelial:mesenchymal transition in gastric cancer: links to soluble HB-EGF, gastrin and matrix metalloproteinase-7. Gut 59 (2010): 1037-1045.
  13. Tsunedomi R, Yoshimura K, Suzuki N, et al. Clinical implications of cancer stem cells in digestive cancers: acquisition of stemness and prognostic impact. Surg Today (2020).
  14. Greaves M. Cancer stem cells: back to Darwin? Semin Cancer Biol 20 (2010): 65-70.
  15. Bessède E, Dubus P, Mégraud F, et al. Helicobacter pylori infection and stem cells at the origin of gastric cancer. Oncogene 34 (2015): 2547-2555.
  16. Choi YJ, Kim N, Chang H, et al. Helicobacter pylori-induced epithelial-mesenchymal transition, a potential role of gastric cancer initiation and an emergence of stem cells. Carcinogenesis 36 (2015): 553-563.
  17. Lee DG, Kim HS, Lee YS, et al. Helicobacter pylori CagA promotes Snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity. Nat Commun 5 (2014): 4423.
  18. Bessède E, Staedel C, Acuña Amador LA, et al. Helicobacter pylori generates cells with cancer stem cell properties via epithelial-mesenchymal transition-like changes. Oncogene 33 (2014): 4123-4131.
  19. Frenck RW Jr. and Clemens J. Helicobacter in the developing world. Microbes Infect 5 (2003): 705-713.
  20. Ford AC, Forman D, Hunt RH, et al. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials. Bmj 348 (2014): 3174.
  21. Lee YC, Chiang TH, Chou CK, et al. Association Between Helicobacter pylori Eradication and Gastric Cancer Incidence: A Systematic Review and Meta-analysis. Gastroenterology 150 (2016): 1113-1124.
  22. Hussein NR. Helicobacter pylori and gastric cancer in the Middle East: a new enigma? World J Gastroenterol 16 (2010): 3226-3234.
  23. Polyak K and Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9 (2009): 265-273.
  24. Pinzani M. Epithelial-mesenchymal transition in chronic liver disease: fibrogenesis or escape from death? J Hepatol 55 (2011): 459-465.
  25. Wu Y and Zhou BP. New insights of epithelial-mesenchymal transition in cancer metastasis. Acta Biochim Biophys Sin (Shanghai) 40 (2008): 643-650.
  26. Thiery JP, Acloque H, Huang RYJ, et al. Epithelial-mesenchymal transitions in development and disease. Cell 139 (2009): 871-890.
  27. Kalluri R and Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 119 (2009): 1420-1428.
  28. Talbot LJ, Bhattacharya SD, and Kuo PC. Epithelial-mesenchymal transition, the tumor microenvironment, and metastatic behavior of epithelial malignancies. Int J Biochem Mol Biol 3 (2012): 117-136.
  29. Chan AO. E-cadherin in gastric cancer. World J Gastroenterol 12 (2006): 199-203.
  30. Liu YC, Shen CY, Wu HS, et al. Helicobacter pylori infection in relation to E-cadherin gene promoter polymorphism and hypermethylation in sporadic gastric carcinomas. World J Gastroenterol 11 (2005): 5174-5179.
  31. Chiba T, Marusawa H, Ushijima T. Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation. Gastroenterology 143 (2012): 550-563.
  32. Ren YH, Liu KJ, Wang M, et al. De-SUMOylation of FOXC2 by SENP3 promotes the epithelial-mesenchymal transition in gastric cancer cells. Oncotarget 5 (2014): 7093-7104.
  33. Guo J, Wang B, Fu Z, et al. Hypoxic Microenvironment Induces EMT and Upgrades Stem-Like Properties of Gastric Cancer Cells. Technol Cancer Res Treat 15 (2016): 60-68.
  34. Sansone P and Bromberg J. Environment, inflammation, and cancer. Curr Opin Genet Dev 21 (2011): 80-85.
  35. Fanelli MF, Chinen LT, Begnami MD, et al. The influence of transforming growth factor-alpha, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial-mesenchymal transition on overall survival of patients with gastric cancer. Histopathology 61 (2012): 153-161.
  36. Chen G, Chen SM, Wang X, et al. Inhibition of chemokine (CXC motif) ligand 12/chemokine (CXC motif) receptor 4 axis (CXCL12/CXCR4)-mediated cell migration by targeting mammalian target of rapamycin (mTOR) pathway in human gastric carcinoma cells. J Biol Chem 287 (2012): 12132-12141.
  37. Oh YS, Kim HY, Song IC, et al. Hypoxia induces CXCR4 expression and biological activity in gastric cancer cells through activation of hypoxia-inducible factor-1alpha. Oncol Rep 28 (2012): 2239-2246.
  38. Zhang J, Zhou Y, and Yang Y. CCR7 pathway induces epithelial-mesenchymal transition through up-regulation of Snail signaling in gastric cancer. Med Oncol 32 (2015): 467.
  39. Ma H, Gao L, Li S, et al. CCR7 enhances TGF-beta1-induced epithelial-mesenchymal transition and is associated with lymph node metastasis and poor overall survival in gastric cancer. Oncotarget 6 (2015): 24348-24360.
  40. Orlichenko LS and Radisky DC. Matrix metalloproteinases stimulate epithelial-mesenchymal transition during tumor development. Clin Exp Metastasis 25 (2008): 593-600.
  41. Huang J, Xiao D, Li G, et al. EphA2 promotes epithelial-mesenchymal transition through the Wnt/beta-catenin pathway in gastric cancer cells. Oncogene 33 (2014): 2737-2747.
  42. Chen J, Wang T, Zhou YC, et al. Aquaporin 3 promotes epithelial-mesenchymal transition in gastric cancer. J Exp Clin Cancer Res 33 (2014): 38.
  43. Palovuori R, Perttu A, Yan Y, et al. Helicobacter pylori induces formation of stress fibers and membrane ruffles in AGS cells by rac activation. Biochem Biophys Res Commun 269 (2000): 247-253.
  44. Tabassam FH, Graham DY, and Yamaoka Y. OipA plays a role in Helicobacter pylori-induced focal adhesion kinase activation and cytoskeletal re-organization. Cell Microbiol 10 (2008): 1008-1020.
  45. Zhang Q, Ding J, Liu J, et al. Helicobacter pylori-infected MSCs acquire a pro-inflammatory phenotype and induce human gastric cancer migration by promoting EMT in gastric cancer cells. Oncol Lett 11 (2016): 449-457.
  46. Buti L, Spooner E, Van der Veen AG, et al. Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host. Proc Natl Acad Sci U S A 108 (2011): 9238-9243.
  47. Hanahan D and Weinberg RA. The hallmarks of cancer. Cell 100 (2000): 57-70.
  48. McNamara D and El-Omar E. Helicobacter pylori infection and the pathogenesis of gastric cancer: a paradigm for host-bacterial interactions. Dig Liver Dis 40 (2008): 504-509.
  49. Camilo V, Sugiyama T, and Touati E. Pathogenesis of Helicobacter pylori infection. Helicobacter 22 (2017).
  50. Censini S, Lange C, Xiang Z, et al. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci U S A 93 (1996): 14648-14653.
  51. Park JY, Forman D, Waskito LA, et al. Epidemiology of Helicobacter pylori and CagA-Positive Infections and Global Variations in Gastric Cancer. Toxins (Basel) 10 (2018): 163.
  52. Higashi H, Tsutsumi R, Muto S, et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295 (2002): 683-686.
  53. Odenbreit S, Puls J, Sedlmaier B, et al. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287 (2000): 1497-1500.
  54. Stein M, Ruggiero P, Rappuoli R, et al. Helicobacter pylori CagA: From Pathogenic Mechanisms to Its Use as an Anti-Cancer Vaccine. Front Immunol 4 (2013): 328.
  55. Choi SI, Yoon C, Park MR, et al. CDX1 Expression Induced by CagA-Expressing Helicobacter pylori Promotes Gastric Tumorigenesis. Mol Cancer Res 17 (2019): 2169-2183.
  56. Bagnoli F, Buti L, Tompkins L, et al. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc Natl Acad Sci U S A 102 (2005): 16339-16344.
  57. Sohn SH and Lee YC. The genome-wide expression profile of gastric epithelial cells infected by naturally occurring cagA isogenic strains of Helicobacter pylori. Environ Toxicol Pharmacol 32 (2011): 382-389.
  58. Li N, Feng Y, Hu Y, et al. Helicobacter pylori CagA promotes epithelial mesenchymal transition in gastric carcinogenesis via triggering oncogenic YAP pathway. J Exp Clin Cancer Res 37 (2018): 280.
  59. Yu H, Zeng J, Liang X, et al. Helicobacter pylori promotes epithelial-mesenchymal transition in gastric cancer by downregulating programmed cell death protein 4 (PDCD4). PLoS One 9 (2014): e105306.
  60. Wu K, Yang L, Li C, et al. MicroRNA-146a enhances Helicobacter pylori induced cell apoptosis in human gastric cancer epithelial cells. Asian Pac J Cancer Prev 15 (2014): 5583-5586.
  61. Tan X, Tang H, Bi J, et al. MicroRNA-222-3p associated with Helicobacter pylori targets HIPK2 to promote cell proliferation, invasion, and inhibits apoptosis in gastric cancer. J Cell Biochem 119 (2018): 5153-5162.
  62. Chang H, Kim N, Park JH, et al. Different microRNA expression levels in gastric cancer depending on Helicobacter pylori infection. Gut Liver 9 (2015): 188-196.
  63. Shi Y, Yang Z, Zhang T, et al. SIRT1-targeted miR-543 autophagy inhibition and epithelial-mesenchymal transition promotion in Helicobacter pylori CagA-associated gastric cancer. Cell Death Dis 10 (2019): 625.
  64. Huang L, Wang ZY, and Pan DD. Penicillinbinding protein 1A mutationpositive Helicobacter pylori promotes epithelialmesenchymal transition in gastric cancer via the suppression of microRNA134. Int J Oncol 54 (2019): 916-928.
  65. Lim H and Moon A. Inflammatory fibroblasts in cancer. Arch Pharm Res 39 (2016): 1021-1031.
  66. Krzysiek-Maczka G, Targosz A, Ptak-Belowska A, et al. Molecular alterations in fibroblasts exposed to Helicobacter pylori: a missing link in bacterial inflammation progressing into gastric carcinogenesis? J Physiol Pharmacol 64 (2013): 77-87.
  67. Krzysiek-Maczka G, Targosz A, Szczyrk U, et al. Role of Helicobacter pylori infection in cancer-associated fibroblast-induced epithelial-mesenchymal transition in vitro. Helicobacter 23 (2018): e12538.
  68. Jin HF, Dai JF, Meng LN, et al. Curcuma wenyujin Y. H. Chen et C. Ling n-Butyl Alcohol Extract Inhibits AGS Cell Helicobacter pyloriCagA+VacA+ Promoted Invasiveness by Down-Regulating Caudal Type Homeobox Transcription Factor and Claudin-2 Expression. Chin J Integr Med 26 (2020): 122-129.
  69. Suganuma M, Kurusu M, Suzuki K, et al. New tumor necrosis factor-alpha-inducing protein released from Helicobacter pylori for gastric cancer progression. J Cancer Res Clin Oncol 131 (2005): 305-313.
  70. Watanabe T, Takahashi A, Suzuki K, et al. Epithelial-mesenchymal transition in human gastric cancer cell lines induced by TNF-alpha-inducing protein of Helicobacter pylori. Int J Cancer 134 (2014): 2373-2382.
  71. Watanabe T, Tsuge H, Imagawa T, et al. Nucleolin as cell surface receptor for tumor necrosis factor-alpha inducing protein: a carcinogenic factor of Helicobacter pylori. J Cancer Res Clin Oncol 136 (2010): 911-921.
  72. Watanabe T, Hirano K, Takahashi A, et al. Nucleolin on the cell surface as a new molecular target for gastric cancer treatment. Biol Pharm Bull 33 (2010): 796-803.
  73. Huber MA, Beug H, and Wirth T. Epithelial-mesenchymal transition: NF-kappaB takes center stage. Cell Cycle 3 (2004): 1477-1480.
  74. Chen G, Tang N, Wang C, et al. TNF-alpha-inducing protein of Helicobacter pylori induces epithelial-mesenchymal transition (EMT) in gastric cancer cells through activation of IL-6/STAT3 signaling pathway. Biochem Biophys Res Commun 484 (2017): 311-317.
  75. Salama NR, Shepherd B, and Falkow S. Global transposon mutagenesis and essential gene analysis of Helicobacter pylori. J Bacteriol 186 (2004): 7926-7935.
  76. Smith TG, Lim JM, Weinberg MV, et al. Direct analysis of the extracellular proteome from two strains of Helicobacter pylori. Proteomics 7 (2007): 2240-2245.
  77. Vallese F, Mishra NM, Pagliari M, et al. Helicobacter pylori antigenic Lpp20 is a structural homologue of Tipalpha and promotes epithelial-mesenchymal transition. Biochim Biophys Acta Gen Subj 1861 (2017): 3263-3271.
  78. Wroblewski LE, Noble PJ, Pagliocca A, et al. Stimulation of MMP-7 (matrilysin) by Helicobacter pylori in human gastric epithelial cells: role in epithelial cell migration. J Cell Sci 116 (2003): 3017-3026.
  79. Bebb JR, Letley DP, Thomas RJ, et al. Helicobacter pylori upregulates matrilysin (MMP-7) in epithelial cells in vivo and in vitro in a Cag dependent manner. Gut 52 (2003): 1408-1413.
  80. Hwang TL, Changchien TT, Wang CC, et al. Claudin-4 expression in gastric cancer cells enhances the invasion and is associated with the increased level of matrix metalloproteinase-2 and -9 expression. Oncol Lett 8 (2014): 1367-1371.
  81. Shan YQ, Ying RC, Zhou CH, et al. MMP-9 is increased in the pathogenesis of gastric cancer by the mediation of HER2. Cancer Gene Ther 22 (2015): 101-107.
  82. Al-Batran SE, Pauligk C, Wirtz R, et al. The validation of matrix metalloproteinase-9 mRNA gene expression as a predictor of outcome in patients with metastatic gastric cancer. Ann Oncol 23 (2012): 1699-1705.
  83. Yeh YC, Sheu BS, Cheng HC, et al. Elevated serum matrix metalloproteinase-3 and -7 in H. pylori-related gastric cancer can be biomarkers correlating with a poor survival. Dig Dis Sci 55 (2010): 1649-1657.
  84. Sakamoto N, Naito Y, Oue N, et al. MicroRNA-148a is downregulated in gastric cancer, targets MMP7, and indicates tumor invasiveness and poor prognosis. Cancer Sci 105 (2014): 236-243.
  85. Hui L and Chen Y. Tumor microenvironment: Sanctuary of the devil. Cancer Lett 368 (2015): 7-13.
  86. Kim J and Bae JS. Tumor-Associated Macrophages and Neutrophils in Tumor Microenvironment. Mediators Inflamm (2016): 6058147.
  87. Krzysiek-Maczka G, Wrobel T, Targosz A, et al. Helicobacter pylori-activated gastric fibroblasts induce epithelial-mesenchymal transition of gastric epithelial cells in vitro in a TGF-beta-dependent manner. Helicobacter 24 (2019): e12653.
  88. Gasparics Á, Kökény G, fintha A, et al. Alterations in SCAI Expression during Cell Plasticity, fibrosis and Cancer. Pathol Oncol Res 24 (2018): 641-651.
  89. Lee KW, Yeo SY, Sung CO, et al. Twist1 is a key regulator of cancer-associated fibroblasts. Cancer Res 75 (2015): 73-85.
  90. Baj J, Brzozowska K, Forma A, et al. Immunological Aspects of the Tumor Microenvironment and Epithelial-Mesenchymal Transition in Gastric Carcinogenesis. Int J Mol Sci 21 (2020): 2544.
  91. Li P, Shan JX, Chen XH, et al. Epigenetic silencing of microRNA-149 in cancer-associated fibroblasts mediates prostaglandin E2/interleukin-6 signaling in the tumor microenvironment. Cell Res 25 (2015): 588-603.
  92. Wu X, Tao P, Zhou Q, et al. IL-6 secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway. Oncotarget 8 (2017): 20741-20750.
  93. Quante M, Tu SP, Tomita H, et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell 19 (2011): 257-272.
  94. Spaeth E, Klopp A, Dembinski J, et al. Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther 15 (2008): 730-738.
  95. Lorger M and Moelling K. Regulation of epithelial wound closure and intercellular adhesion by interaction of AF6 with actin cytoskeleton. J Cell Sci 119 (2006): 3385-3398.
  96. Takai Y, Miyoshi J, Ikeda W, et al. Nectins and nectin-like molecules: roles in contact inhibition of cell movement and proliferation. Nat Rev Mol Cell Biol 9 (2008): 603-615.
  97. Marques MS, Melo J, Cavadas B, et al. Afadin Downregulation by Helicobacter pylori Induces Epithelial to Mesenchymal Transition in Gastric Cells. Front Microbiol 9 (2018): 2712.
  98. Zhou S, Chen H, Yuan P, et al. Helicobacter pylori infection promotes epithelial-to-mesenchymal transition of gastric cells by upregulating LAPTM4B. Biochem Biophys Res Commun 514 (2019): 893-900.
  99. Kim N. Chemoprevention of gastric cancer by Helicobacter pylori eradication and its underlying mechanism. J Gastroenterol Hepatol 34 (2019): 1287-1295.
  100. Chang H, Kim N, Park JH, et al. Helicobacter pylori Might Induce TGF-beta1-Mediated EMT by Means of cagE. Helicobacter 20 (2015): 438-448.
  101. Ling ZQ, Guo W, Lu XX, et al. A Golgi-specific protein PAQR3 is closely associated with the progression, metastasis and prognosis of human gastric cancers. Ann Oncol 25 (2014): 1363-1372.
  102. Bessède E, Molina S, Acuña-Amador L, et al. Deletion of IQGAP1 promotes Helicobacter pylori-induced gastric dysplasia in mice and acquisition of cancer stem cell properties in vitro. Oncotarget 7 (2016): 80688-80699.

Grant Support Articles

© 2016-2022, Copyrights Fortune Journals. All Rights Reserved!