Explore the vast range of titles available.

Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor of gastric cancer. The cagA gene-encoded CagA protein is delivered into gastric epithelial cells via bacterial type IV secretion, where it undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs. Delivered CagA then acts as a non-physiological scaffold/hub protein by interacting with multiple host signaling molecules, most notably the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1/MARK, in both tyrosine phosphorylation-dependent and -independent manners. CagA-mediated manipulation of intracellular signaling promotes neoplastic transformation of gastric epithelial cells. Transgenic expression of CagA in experimental animals has confirmed the oncogenic potential of the bacterial protein. Structural polymorphism of CagA influences its scaffold function, which may underlie the geographic difference in the incidence of gastric cancer. Since CagA is no longer required for the maintenance of established gastric cancer cells, studying the role of CagA during neoplastic transformation will provide an excellent opportunity to understand molecular processes underlying “Hit-and-Run” carcinogenesis.

Gastric carcinoma is the second leading cause of cancer-related deaths in the world, accounting for more than 700,000 deaths each year. Recent studies have revealed that infection with cagA-positive Helicobacter pylori plays an essential role in the development of gastric carcinoma. The cagA-encoded CagA protein is delivered into gastric epithelial cells via the bacterial type IV secretion system, where it undergoes tyrosine phosphorylation by Src and Abl kinases. Tyrosine-phosphorylated CagA then acquires the ability to interact with and deregulate SHP-2 phosphatase, a bona-fide oncoprotein, deregulation of which is involved in a variety of human malignancies. CagA also binds to and inhibits PAR1b/MARK2 polarity-regulating kinase to disrupt tight junctions and epithelial apical-basolateral polarity. These CagA activities may collectively contribute to the transformation of gastric epithelial cells. Indeed, transgenic expression of CagA in mice results in the development of gastrointestinal and hematological malignancies, indicating that CagA is the first bacterial oncoprotein that acts in mammalian cells. The oncogenic potential of CagA may be further potentiated in the presence of chronic inflammation, which aberrantly induces activation-induced cytidine deaminase (AID), a member of the DNA/RNA-editing enzyme family. Ectopically expressed AID may contribute to H. pylori-initiated gastric carcinogenesis by increasing the risk of likelihood of epithelial cells acquiring mutations in cancer-related genes.

Infection with cagA‐positive Helicobacter pylori strains plays an etiological role in the development of gastric cancer. The CagA protein is injected into gastric epithelial cells through a bacterial Type IV secretion system. Inside the host cells, CagA promiscuously associates with multiple host cell proteins including the prooncogenic phosphatase SHP2 that is required for full activation of the Ras–ERK pathway. CagA–SHP2 interaction aberrantly activates SHP2 and thereby deregulates Ras–ERK signaling. Cancer is regarded as a disease of the genome, indicating that H. pylori‐mediated gastric carcinogenesis is also associated with genomic alterations in the host cell. Indeed, accumulating evidence has indicated that H. pylori infection provokes DNA double‐stranded breaks (DSBs) by both CagA‐dependent and CagA‐independent mechanisms. DSBs are repaired by either error‐free homologous recombination (HR) or error‐prone non‐homologous end joining (NHEJ) or microhomology‐mediated end joining (MMEJ). Infection with cagA‐positive H. pylori inhibits RAD51 expression while dampening cytoplasmic‐to‐nuclear translocalization of BRCA1, causing replication fork instability and HR defects (known as “BRCAness”), which collectively provoke genomic hypermutation via non‐HR‐mediated DSB repair. H. pylori also subverts multiple DNA damage responses including DNA repair systems. Infection with H. pylori additionally inhibits the function of the p53 tumor suppressor, thereby dampening DNA damage‐induced apoptosis, while promoting proliferation of CagA‐delivered cells. Therefore, H. pylori cagA‐positive strains promote abnormal expansion of cells with BRCAness, which dramatically increases the chance of generating driver gene mutations in the host cells. Once such driver mutations are acquired, H. pylori CagA is no longer required for subsequent gastric carcinogenesis (Hit‐and‐Run carcinogenesis). The review article summarizes recent advances in our understanding the mechanism by which the bacterial carcinogen H. pylori promote gastric carcinogenesis. Especially, the review article focuses on the relationship between the H. pylori oncoprotein CagA and genome instability.

Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer. The cagA gene product, CagA, is delivered into gastric epithelial cells via the bacterial type IV secretion system. Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and -independent manners. Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks: sustained proliferation, evasion of growth suppressors, invasiveness, resistance to cell death, and genomic instability. Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation. The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation. Since Helicobacter pylori infection triggers a proinflammatory response in host cells, a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa. Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions, the multistep nature of gastric cancer development should include a “hit-and-run” process of CagA action. Thus, acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the “hit-and-run” process of gastric carcinogenesis.

Helicobacter pylori CagA is the first bacterial oncoprotein to be identified in relation to human cancer. CagA is delivered into gastric epithelial cells through a bacterial type IV secretion system and localizes to the plasma membrane, where it undergoes tyrosine phosphorylation by host cell kinases. Membrane‐localized CagA then mimics mammalian scaffold proteins and perturbs a number of host signaling pathways in both tyrosine phosphorylation‐dependent and ‐independent manners, thereby promoting transformation of gastric epithelial cells. Helicobacter pylori CagA is noted for structural diversity in its C‐terminal region, with which CagA interacts with numerous host cell proteins. This CagA polymorphism is primarily due to differential combination and alignment of the four distinct EPIYA segments and the two different CagA‐multimerization sequences in making the C‐terminal region. The structural diversity substantially influences the pathophysiological action of CagA. This review focuses on the molecular basis for the structural polymorphism that determines the degrees of virulence and oncogenic potential of individual CagA. The pylogeographic distribution of differential CagA isoforms is also discussed in the context of human migration history, which may underlie large geographical variations in the incidence of gastric cancer in different parts of the world. (Cancer Sci 2011; 102: 36–43)

Key Points Gastric carcinoma is the second most common cause of cancer-related death worldwide. Chronic infection with Helicobacter pylori that carries the cytotoxin-associated antigen A ( cagA ) gene is associated with gastric carcinoma. The cagA gene product, CagA, is delivered into gastric epithelial cells by the bacterial type IV secretion system and undergoes tyrosine phosphorylation by SRC family kinases. Tyrosine phosphorylation occurs at EPIYA motifs on CagA. Phosphorylated CagA specifically binds and activates SHP2, the first phosphatase found to act as a human oncoprotein. As SHP2 transmits positive signals for cell growth and motility, deregulation of SHP2 by CagA is an important mechanism by which cagA -positive H. pylori promotes gastric carcinogenesis. CagA is noted for its variation at the SHP2 binding site and, based on the sequence variation, is subclassified into two main types — East-Asian CagA and Western CagA. East-Asian CagA shows stronger SHP2 binding and greater biological activity than Western CagA. In East-Asian countries, endemic circulation of H. pylori strains that carry biologically active forms of CagA might underlie the high incidence of gastric carcinoma. Infection with strains of Helicobacter pylori that carry the cytotoxin-associated antigen A ( cagA ) gene is associated with gastric carcinoma. Recent studies have shed light on the mechanism through which the cagA gene product, CagA, elicits pathophysiological actions. CagA is delivered into gastric epithelial cells by the bacterial type IV secretion system, where it deregulates the SHP2 oncoprotein. Intriguingly, CagA is noted for its variation, particularly at the SHP2-binding site, which could affect the potential of different strains of H. pylori to promote gastric carcinogenesis.

In most cases of sporadic colorectal cancers, tumorigenesis is a multistep process, involving genomic alterations in parallel with morphologic changes. In addition, accumulating evidence suggests that the human gut microbiome is linked to the development of colorectal cancer. Here we performed fecal metagenomic and metabolomic studies on samples from a large cohort of 616 participants who underwent colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites. Microbiome and metabolome shifts were apparent in cases of multiple polypoid adenomas and intramucosal carcinomas, in addition to more advanced lesions. We found two distinct patterns of microbiome elevations. First, the relative abundance of Fusobacterium nucleatum spp. was significantly (P < 0.005) elevated continuously from intramucosal carcinoma to more advanced stages. Second, Atopobium parvulum and Actinomyces odontolyticus, which co-occurred in intramucosal carcinomas, were significantly (P < 0.005) increased only in multiple polypoid adenomas and/or intramucosal carcinomas. Metabolome analyses showed that branched-chain amino acids and phenylalanine were significantly (P < 0.005) increased in intramucosal carcinomas and bile acids, including deoxycholate, were significantly (P < 0.005) elevated in multiple polypoid adenomas and/or intramucosal carcinomas. We identified metagenomic and metabolomic markers to discriminate cases of intramucosal carcinoma from the healthy controls. Our large-cohort multi-omics data indicate that shifts in the microbiome and metabolome occur from the very early stages of the development of colorectal cancer, which is of possible etiological and diagnostic importance.Colorectal cancer stages are associated with distinct microbial and metabolomic profiles that could shed light on cancer progression.

Infection with cagA‐positive Helicobacter pylori is associated with the development of gastric adenocarcinoma. The cagA gene product CagA is injected directly from the bacterium into the bacterium‐attached gastric epithelial cells via the type‐IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, CagA functions as a scaffolding adaptor and interacts with a number of host proteins that regulate cell growth, cell motility and cell polarity in both CagA phosphorylation‐dependent and phosphorylation‐independent manners. Of special interest is the interaction of CagA with the SHP‐2 tyrosine phosphatase, gain‐of‐function mutations that of which have recently been found in a variety of human malignancies. The CagA–SHP‐2 interaction is entirely dependent on CagA tyrosine phosphorylation and, through the complex formation, SHP‐2 is catalytically activated and induces morphological transformation with elevated cell motility. Intriguingly, structural diversity of the tyrosine phosphorylation sites of CagA accounts for the differential activity of individual CagA to bind and activate SHP‐2. Deregulation of SHP‐2 and other intracellular signaling molecules by H. pylori CagA may predispose cells to accumulate multiple genetic and epigenetic changes involved in gastric carcinogenesis. Furthermore, the differential potential of individual CagA to disturb cellular functions indicates that H. pylori strains carrying biologically more active CagA are more virulent than those with less active CagA and are more closely associated with gastric carcinoma. (Cancer Sci 2005; 96: 835–843)

Infection with Helicobacter pylori is known to confer a risk of gastric cancer. In this study, persons who carried certain genetic variants and were infected with H. pylori had an excess risk of gastric cancer.

Chronic infection with Helicobacter pylori cagA‐positive strains is causally associated with the development of gastric diseases, most notably gastric cancer. The cagA‐encoded CagA protein, which is injected into gastric epithelial cells by bacterial type IV secretion, undergoes tyrosine phosphorylation at the Glu‐Pro‐Ile‐Tyr‐Ala (EPIYA) segments (EPIYA‐A, EPIYA‐B, EPIYA‐C, and EPIYA‐D), which are present in various numbers and combinations in its C‐terminal polymorphic region, thereby enabling CagA to promiscuously interact with SH2 domain‐containing host cell proteins, including the prooncogenic SH2 domain‐containing protein tyrosine phosphatase 2 (SHP2). Perturbation of host protein functions by aberrant complex formation with CagA has been considered to contribute to the development of gastric cancer. Here we show that SHIP2, an SH2 domain‐containing phosphatidylinositol 5′‐phosphatase, is a hitherto undiscovered CagA‐binding host protein. Similar to SHP2, SHIP2 binds to the Western CagA‐specific EPIYA‐C segment or East Asian CagA‐specific EPIYA‐D segment through the SH2 domain in a tyrosine phosphorylation‐dependent manner. In contrast to the case of SHP2, however, SHIP2 binds more strongly to EPIYA‐C than to EPIYA‐D. Interaction with CagA tethers SHIP2 to the plasma membrane, where it mediates production of phosphatidylinositol 3,4‐diphosphate [PI(3,4)P2]. The CagA‐SHIP2 interaction also potentiates the morphogenetic activity of CagA, which is caused by CagA‐deregulated SHP2. This study indicates that initially delivered CagA interacts with SHIP2 and thereby strengthens H. pylori‐host cell attachment by altering membrane phosphatidylinositol compositions, which potentiates subsequent delivery of CagA that binds to and thereby deregulates the prooncogenic phosphatase SHP2. The SH2 domain‐containing phosphatidylinositol 5′‐phosphatase, SHIP2, is a hitherto undiscovered CagA‐binding host protein. The CAgA‐SHIP2 interaction potentiates Helicobacter pylori‐mediated CagA delivery into gastric epithelial cells, which then promotes the formation of the oncogenic CagA‐SHP2 complex.