Christine Varon

INSERM U1312 BRIC Bordeaux Institute of Oncology, Université de Bordeaux

Background Cancer stem cells (CSCs) are at the origin of tumour initiation and progression in gastric adenocarcinoma (GC). However, markers of metastasis-initiating cells remain unidentified in GC. In this study, we characterized CD44 variants expressed in GC and evaluated the tumorigenic and metastatic properties of CD44v3+ cells and their clinica...

Background: Gastric cancer, the fifth most common cancer worldwide, is mainly linked to Helicobacter pylori infection. H. pylori induces chronic inflammation of the gastric mucosa associated with high oxidative stress. Our study aimed at assessing the implication of Nrf2, a major regulator of cellular redox homeostasis, in H. pylori-induced gastri...

Background: Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. The enteric nervous system (ENS) has been suggested to be involved in cancer development and spread. Objective: To analyze the GC cell adhesion to the ENS in a model of co-culture of gastric ENS with GC cells. Methods: Primary culture of gastric ENS...

The Hippo pathway is one of the most important ones in mammals. Its key functions in cell proliferation, tissue growth, repair, and homeostasis make it the most crucial one to be controlled. Many means have been deployed for its regulation, since this pathway is not only composed of core regulatory components, but it also communicates with and regu...

We are frequently exposed to bacterial genotoxins, such as cytolethal distending toxin (CDT), a prevalent heterotrimeric toxin whose active moiety is its CdtB subunit. CdtB triggers potent DNA damage, predisposing factors in the development of cancers, in host cells. CDT from Helicobacter hepaticus , a mouse pathogen, was shown to be directly invol...

IL-6 family cytokine leukaemia inhibitory factor (LIF) study has deciphered a variety of effects, in physiology as well as pathology. Despite the sudden arousal in LIF interest in cancers, its study in the gastric cancer (GC) context has been put aside. Only few related studies can be found in literature, most of them investigating IL-6/STAT3 signa...

Glutamoptosis is the induction of apoptotic cell death as a consequence of the aberrant activation of glutaminolysis and mTORC1 signaling during nutritional imbalance in proliferating cells. The role of the bioenergetic sensor AMPK during glutamoptosis is not defined yet. Here, we show that AMPK reactivation blocks both the glutamine-dependent acti...

The Helicobacter genus actually comprises 46 validly published species divided into two main clades: gastric and enterohepatic Helicobacters. These bacteria colonize alternative sites of the digestive system in animals and humans, and contribute to inflammation and cancers. In humans, Helicobacter infection is mainly related to H. pylori, a gastric...

Gastric cancer's bad incidence, prognosis, cellular and molecular heterogeneity amongst others make this disease a major health issue worldwide. Understanding this affliction is a priority for proper patients' management and for the development of efficient therapeutical strategies. This review gives an overview of major scientific advances, made d...

Cancer is a complex disease and it is now clear that not only epithelial tumor cells play a role in carcinogenesis. The tumor microenvironment is composed of non-stromal cells, including endothelial cells, adipocytes, immune and nerve cells, and a stromal compartment composed of extracellular matrix, cancer-associated fibroblasts and mesenchymal ce...

Background: The main cause of gastric cancer is the infection by the bacterium Helicobacter pylori which induces a chronic inflammation and an epithelial-to-mesenchymal transition (EMT) leading to the emergence of cells with cancer stem cell (CSC) properties. However, the underlying mechanisms have not been fully characterized. Moreover, H. pylori...

Cancer stem cells (CSCs) present chemo-resistance mechanisms contributing to tumour maintenance and recurrence, making their targeting of utmost importance in gastric cancer (GC) therapy. The Hippo pathway has been implicated in gastric CSC properties and was shown to be regulated by leukaemia inhibitory factor receptor (LIFR) and its ligand LIF in...

Helicobacter pylori infection, the main risk factor for gastric cancer (GC), leads to an epithelial–mesenchymal transition (EMT) of gastric epithelium contributing to gastric cancer stem cell (CSC) emergence. The Hippo pathway effectors yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) control cancer initiat...

Despite extensive research, the origin of Alzheimer's disease (AD) remains unknown. The role of infectious pathogens has recently emerged. Epidemiological studies have shown that Helicobacter pylori infection increases the risk of developing AD. We hypothesized that H. pylori-induced gastritis may be associated with a systemic inflammation and fina...

The present study describes three putative novel species received at the French National Reference Center for Campylobacters & Helicobacters (CNRCH). The CNRCH 2005/566H strain was isolated in 2005 from the feces of a patient between 55 and 60 years old with a hepatocellular carcinoma and gastroenteritis. Strain 48519 was isolated in 2017 from the...

Background & aims: Gastric carcinoma (GC) is mostly related to CagA+-Helicobacter pylori infection, which disrupts the gastric mucosa turnover and elicits an epithelial-mesenchymal transition (EMT) and preneoplastic trans-differentiation. The tumor suppressor Hippo pathway controls stem cell homeostasis; its core, constituted by the LATS2 kinase a...

Humans are frequently exposed to bacterial genotoxins involved in digestive cancers, colibactin and Cytolethal Distending Toxin (CDT), the latter being secreted by many pathogenic bacteria. Our aim was to evaluate the effects induced by these genotoxins on nuclear remodeling in the context of cell survival. Helicobacter infected mice, coculture exp...

Gastric carcinomas (GC) are heterogeneous tumours, composed of a subpopulation of CD44+ tumorigenic and chemo‐resistant cancer stem cells (CSC). YAP1 and TAZ oncoproteins (Y/T) interact with TEAD transcription factors to promote cell survival and proliferation in multiple tissues. Their activity and role in GC remain unclear. This work aimed to ana...

Gastric cancer is the third leading cause of cancer mortality worldwide. Cancer stem cells (CSC) are at the origin of tumor initiation, chemoresistance, and the formation of metastases. However, there is a lack of mouse models enabling the study of the metastatic process in gastric adenocarcinoma (GC). The aims of this study were to develop origina...

Aim: Helicobacter pylori infection is a worldwide infection, its eradication rates with conventional therapies have fallen to unacceptable levels. In this context we were interested in metformin, to determine its effect on H. pylori growth. Materials & methods: Antimicrobial susceptibility tests and survival curves were performed in vitro and a...

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide with a five-year survival rate of around 25%, and 4% when diagnosed at a metastatic stage. Cancer stem cells (CSC) have recently been characterized as being responsible for resistance to radio/chemotherapies and metastasis formation, opening up perspectives for new tar...

Background: Helicobacter pylori are stomach-dwelling bacteria that are present in about 50% of the global population. Infection is asymptomatic in most cases, but it has been associated with gastritis, gastric ulcers and gastric cancer. Epidemiological evidence shows that progression to cancer depends upon the host and pathogen factors, but questi...

Gastric cancer is the third leading cause of cancer-related death worldwide, but the mechanisms of gastric carcinogenesis are not completely understood. Recently, the role of cholinergic neuronal pathways in promoting this process has been demonstrated. Our aim was to extend these studies and to evaluate, using an in vitro model of tumorspheres, th...

Gastric carcinoma is the third leading cause of cancer-related death worldwide. This cancer, most of the time metastatic, is essentially treated by surgery associated with conventional chemotherapy, and has a poor prognosis. The existence of cancer stem cells (CSC) expressing CD44 and a high aldehyde dehydrogenase (ALDH) activity has recently been...

Gastric cancer is one of the most incident and deadliest malignancies in the world. Gastric cancer is a heterogeneous disease and the end point of a long and multistep process, which results from the stepwise accumulation of numerous (epi)genetic alterations, leading to dysregulation of oncogenic and tumor suppressor pathways. Gastric cancer stem c...

Gastric cancer is the third leading cause of cancer-related deaths worldwide and has still a poor prognosis. Therefore, new therapeutic strategies are needed: among them, targeting cancer stem cells (CSCs) could offer new opportunities. The aim of our study was to evaluate the anti-tumoural effect of metformin on gastric cancer in vitro and in vivo...

Cytolethal distending toxins (CDTs) are common among pathogenic bacteria of the human and animal microbiota. CDTs exert cytopathic effets, via their active CdtB subunit. No clear description of those cytopathic effects has been reported at the cellular level in the target organs in vivo. In the present study, xenograft mouse models of colon and liv...

Purpose: Gastric carcinomas (GC) are heterogeneous, and the current therapy remains essentially based on surgery with conventional chemo- and radiotherapy. This study aimed to characterize biomarkers allowing the detection of cancer stem cells (CSC) in human GC of different histological types. Experimental design: The primary tumors from thirty-...

Helicobacter pylori infection is responsible for gastric carcinogenesis but host factors are also implicated. IQGAP1, a scaffolding protein of the adherens junctions interacting with E-cadherin, regulates cellular plasticity and proliferation. In mice, IQGAP1 deficiency leads to gastric hyperplasia. The aim of this study was to elucidate the conseq...

Gastric carcinoma is the third leading cause of cancer-related death worldwide. This cancer, most of the time metastatic, is essentially treated by surgery associated with conventional chemotherapy, and has a poor prognosis. The existence of cancer stem cells (CSC) expressing CD44 and a high aldehyde dehydrogenase (ALDH) activity has recently been...

Alzheimer's disease (AD) is associated with Aß peptide and Tau protein deposits, but the initial process inducing the disease and ultimately neurodegeneration has not yet been elucidated. An infectious hypothesis is suggested by the alteration of the blood-brain barrier and the activation of neuroinflammation in the brain, which could play a role,...

Enterohepatic Helicobacters are associated with several digestive diseases. Helicobacter pullorum is an emerging human foodborne pathogen and Helicobacter hepaticus is a mouse pathogen; both species are associated with intestinal and/or hepatic diseases. They possess virulence factors such as the cytolethal distending toxin (CDT). Data indicates th...

Several hypotheses are proposed for understanding the Alzheimer's disease (AD) pathological mechanisms, mainly the amyloid theory, but the process inducing Aß peptide deposit, tau protein degeneration, and ultimately neuronal loss, is still to be elucidated. Alteration of the blood-brain barrier and activation of neuroinflammation seem to play an i...

The use of natural products of plant base has been considerable interest in the treatment of human diseases specifically cancer. Therefore, the purpose of this study was to determine whether methanolic extracts obtained from Pistacia lentiscus collected in the north of Tunisia, contain components capable of inhibiting the growth of the human colon...

MicroRNAs regulate eukaryotic gene expression upon pairing onto target mRNAs. This targeting is influenced by the complementarity between the microRNA "seed" sequence at its 5' end and the seed-matching sequences in the mRNA. Here, we assess the efficiency and specificity of 8-mer locked nucleic acid (LNA)-modified oligonucleotides raised against t...

Helicobacter pylori infection is considered to be the main cause of gastric cancer and the most frequent infection-induced cancer. H. pylori is a heterogeneous species which can harbour pathogenic factors such as a cytotoxin, a pathogenicity island (cag) encoding a type 4 secretion system, and the first bacterial oncoprotein: CagA. This oncoprotein...

There is increasing evidence to support the role of infectious agents in the progression of Alzheimer's disease (AD), especially Helicobacter pylori (H. pylori). The impact of Helicobacter infection on the brain of non-AD predisposed mice was studied. For that, C57BL/6J mice were infected by oral gavage with H. pylori SS1 (n = 6) and Helicobacter f...

Helicobacter pylori is a Gram-negative, microaerophilic bacterium which colonises human gastric mucosa. Initially, B. Marshall and W. Warren discovered the etiological role of H. pylori in gastritis and peptic ulcers and received the Nobel Prize in Medicine in 2005. Indeed, since 1994, H. pylori has been also recognised by the WHO to be associated...

Helicobacter pylori infection is now recognized as the main and specific infectious cause of cancer in the world. It is responsible for gastric adenocarcinomas of both intestinal and diffuse types, which are the long-term consequences of the chronic infection of the gastric mucosa. Case-control studies have shown an association between the two, rec...

Neonatal thymectomy in BALB/c mice has been described as a model of gastric MALT lymphoma (GML). By using this experimental system, we screened, for the first time to our knowledge, Helicobacter pylori GML-associated strains for their capacity to promote disease. A cohort of BALB/c mice underwent thymectomy at day 3 after birth (d3Tx). Successful t...

Possible recombination process of how v225d CagA has evolved.

Helicobacter pullorum, a bacterium initially isolated from poultry, has been associated with human digestive disorders. However, the factor responsible for its cytopathogenic effects on epithelial cells has not been formally identified. The cytopathogenic alterations induced by several human and avian H. pullorum strains were investigated on human...

Helicobacter pylori strains carrying the cagA gene are associated with severe disease outcomes, most notably gastric cancer. CagA protein is delivered into gastric epithelial cells by a type IV secretion system. The translocated CagA undergoes tyrosine phosphorylation at the C-terminal EPIYA motifs by host cell kinases. Tyrosine-phosphorylated CagA...

Helicobacter pylori infection is now recognized as the main infection attributable cause of cancer in the world. It is responsible for most of the gastric adenocarcinomas of intestinal as well as diffuse type, which are the long term consequence of a chronic infection of the gastric mucosa. Case control stu-dies have shown an association already re...

Helicobacter pylori infection is the major risk factor for gastric adenocarcinoma. The link with gastric adenocarcinoma is partly due to the H. pylori CagA oncoprotein. CagA is responsible for a particular cell phenotype in vitro, the 'hummingbird' phenotype, that corresponds to an elongation of the cells, mimicking an epithelial-mesenchymal transi...

Chronic Helicobacter pylori infection provokes an inflammation of the gastric mucosa, at high risk for ulcer and cancer development. The most virulent strains harbor the cag pathogenicity island (cagPAI) encoding a type 4 secretion system, which allows delivery of bacterial effectors into gastric epithelial cells, inducing pro-inflammatory response...

Post-transcriptional regulation of ZEB1 expression by miR-200b&c. (A) Inverse relationship between miR-200b&c and ZEB1 expressions in human cell lines. Upper panel, endogenous expression of mature miR-200b or-200c determined by RT-qPCR; bars indicate mean ± SD of miRNA expression normalized to U6 snRNA (n = 5). Lower panels, ZEB1 and tubulin immuno...

Up-regulation of miR-200b and miR-200c in MKN-74 and NCI-N87 cells 24 h post infection with cagPAI+ H. pylori (Hp WT) at MOI 100 bacteria/cell. Bars represent mean ± SD of RTqPCR data for miR-200b or miR-200b relative to U6 snRNA and compared to non infected cells (NI); n = 4, *: p-value <0.05; **, p<0.01; ***, p<0.001. (DOCX)

MiR-200b-200a-429 promoter activity. (A) MiR-200b-200a-429 promoter activity in HEK293, AGS or MKN-74 cells measured by the promoter luciferase reporter; upper panel, bars represent mean ± SD of the luciferase activity of the miRNA promoter relative to that of SV40 promoter reporter (n = 2); lower panel, ZEB1 and tubulin immunoblots. (B) SV40 promo...

E-cadherin immunolabeling in NCI-N87 cells in basal conditions (left panel) or upon infection with wild type H. pylori at MOI100 (right panel). Cell were fixed and labeled stepwise with a anti-E-cadherin monoclonal antibody (1/1,600 dilution, Sigma, France), and then with a mixture containing a AlexaFluor 488-labeled anti-mouse secondary antibody (...

NF-κB immunofluorescence in AGS cells transfected with pEGFP (left panels) or pEGFP-IκB (right panels) in basal conditions or upon infection. Cells were seeded in 8-well Labteck™ chambers and transfected with the expression vectors at 100 ng/well. Forty eight hrs post-transfection, cells were infected with wild type H. pylori at MOI 100. Six hrs la...

List of oligonucleotide primers. (DOCX)

Expression of the miR-200 family members in gastric epithelial cell lines. (A) Levels of miR-200 in basal conditions: values represent mean ± SD of RT-qPCR data for each miRNA relative to snoR25 (n = 4). (B) Variations of miR-200a, -429 and -141, 24 h post-infection with cagPAI+ H. pylori (Hp WT) or the isogenic CagA-deficient strain, both at MOI 1...

Cell morphology of AGS, MKN74 or NCI-N87 cells, not infected (NI) or upon 24 h infection with either cagPAI+ wild type H. pylori (Hp WT) or its isogenic mutants deleted either for cagA (Hp ΔCagA) or cagE (Hp ΔCagE), each at MOI 100 bacteria/cell. In Hp WT-infected AGS or NCI-N87 cells, cells with typical mesenchymal phenotype are highlighted. Hp WT...

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