Helicobacter pylori CagA upregulation of CIP2A is dependent on the Src and MEK/ERK pathways

Abstract

Helicobacter pylori is classified as a class I carcinogenic factor and its persistent colonization in the stomach induces gastric cancer. Cancerous Inhibitor of PP2A (CIP2A) is a newly identified oncoprotein overexpressed in gastric cancer. Serving as a key oncoprotein, CIP2A also participates in regulation of senescence and proliferation of gastric cells. The combination of aberrant CIP2A expression inducing unlimited cell proliferation, and H. pylori infection eliciting aberrant expression of some key proteins, results in the onset of gastric tumorigenesis. However, the relationship between H. pylori infection and CIP2A expression still remains undefined. The aim of our study was to verify the effect of H. pylori infection on CIP2A expression levels and identify H. pylori signalling molecules and corresponding pathways influencing CIP2A expression. Following plasmid-mediated expression of CagA in human gastric cell lines, the cells were infected with H. pylori and CIP2A expression levels were examined by immunoblotting. Signal inhibitors were used to verify which signal pathways were involved. We also performed CIP2A depletion and H. pylori infection after depletion in AGS cells. H. pylori infection-induced CIP2A expression was dependent on cagA gene expression and CagA phosphorylation. Bacterial oncoprotein CagA upregulated CIP2A expression and this upregulation effect was dependent on Src and Ras/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways. H. pylori infection-induced Myc stabilization was partially attenuated by CIP2A depletion. The results of our study provide further information for understanding the mechanism of H. pylori carcinogenesis. INTRODUCTIONHelicobacter pylori has been defined as a class I carcinogenic factor by the World Health Organization and its persistent colonization in the stomach leads to an increased risk of peptic ulcers and gastric adenocarcinoma (Houghton & Wang, 2005;Peek & Blaser, 2002). Some H. pylori strains contain a 35-40 kb cag pathogenicity island (PAI) encoded by 27-33 genes (Akopyants et al., 1998;Azuma et al., 2004). One constituent of the cag PAI is cagA, which encodes a 120-140 kDa CagA protein. CagA protein, which has tyrosine phosphorylation (EPIYA) motifs, is injected into gastric epithelial cells by the type IV secretory system (TFSS) (Odenbreit et al., 2000;Stein et al., 2000). cagApositive H. pylori strains have a closer association with the progress of both peptic ulcers and gastric cancer than cagAnegative strains according to epidemiological research (Hatakeyama, 2003). Within gastric epithelial cells, tyrosine phosphorylation occurs at the C terminus of CagA by the Src family of tyrosine kinases (Kwok et al., 2007; Stein et al., 2002). CagA interacts with many signal molecules and elicits a series of cellular events. These events include activation of the Ras/mitogen-activated protein (MAP) kinase kinase (MEK)/ extracellular signal-regulated kinase (ERK) pathway, bcatenin, Src kinase, the NF-kB pathway and the p38 MAP...

Helicobacter pylori enhances CIP2A expression and cell proliferation via JNK2/ATF2 signaling in human gastric cancer cells

“…In addition to activating MAPK, H. pylori infection also induces the expression of other inflammatory responsive genes including nuclear factor-κB (NF-κB) (8), cyclooxygenase-2 (COX-2) (9) and aquaporin 3 (AQP3) (10). H. pylori has been reported to stimulate the proliferation of gastric epithelial cells both in vitro and in vivo (5,11,12) and to alter intercellular tight junctions (13), thus facilitating the malignant transformation of the gastric mucosa.…”

TD-19, an Erlotinib Derivative, Induces Epidermal Growth Factor Receptor Wild-Type Nonsmall-Cell Lung Cancer Apoptosis through CIP2A-Mediated Pathway

“…We discovered that TD-19 enhanced PP2A activity by suppressing CIP2A and subsequently reduced p-AKT expression through depletion of CIP2A transcriptional activity. Several reports previously demonstrated that there are different ways to modulate CIP2A expression: e.g., upregulation of CIP2A by the Src and Ras/mitogen-activated protein kinase/ extracellular signal-regulated kinase pathways (Jung et al, 2013), repression of CIP2A by microRNA that binds to the coding region of CIP2A (Zhao et al,2010), and use of transcription factors that interact with CIP2A proximal promoters to regulate CIP2A expression (Khanna et al, 2011;Pallai et al, 2012). Our study demonstrated that TD-19 induced cell death and apoptosis by attenuation of CIP2A signaling through decreased transcription of CIP2A.…”

Inflammation and proliferation – a causal event of host response to Helicobacter pylori infection

“…Moreover, when phosphorylated, ERK (pERK) translocates to the nucleus, which can result in the activation of other transcription factors, including activator protein-1, which when bound to the IL-8 promoter region would lead to maximal gene expression (Asim et al, 2010;Hoffmann et al, 2002). The role of CagA in ERK activation has been studied previously (Zhao et al, 2010). As shown in Fig.…”