Although most H. pylori infectors are asymptomatic, some may develop serious disease, such as gastric adenocarcinoma, gastric high-grade B cell lymphoma and peptic ulcer disease. Epidemiological and basic studies have provided evidence that infection with H. pylori carrying specific virulence factors can lead to more severe outcome. The virulence factors that are associated with gastric adenocarcinoma development include the presence, expression intensity and types of cytotoxin-associated gene A (CagA, especially EPIYA-D type and multiple copies of EPIYA-C) and type IV secretion system (CagL polymorphism) responsible for its translocation into the host cells, the genotypes of vacuolating cytotoxin A (vacA, s1/i1/m1 type), and expression intensity of blood group antigen binding adhesin (BabA, low-producer or chimeric with BabB). The presence of CagA is also related to gastric high-grade B cell lymphoma occurrence. Peptic ulcer disease is closely associated with cagA-genopositive, vacA s1/m1 genotype, babA2-genopositive (encodes BabA protein), presence of duodenal ulcer promoting gene cluster (dupA cluster) and induced by contact with epithelium gene A1 (iceA1), and expression status of outer inflammatory protein (OipA). The prevalence of these virulence factors is diverse among H. pylori isolated from different geographic areas and ethnic groups, which may explain the differences in disease incidences. For example, in East Asia where gastric cancer incidence is highest worldwide, almost all H. pylori isolates were cagA genopositive, vacA s1/i1/m1 and BabA-expressing. Therefore, selection of appropriate virulence markers and testing methods are important when using them to determine risk of diseases. This review summarizes the evidences of H. pylori virulence factors in relation with gastroduodenal diseases and discusses the geographic differences and appropriate methods of analyzing these virulence markers.

Discoidin domain receptor 1 (DDR1) promotes cell differentiation through the increase of E-cadherin-mediated cell-cell contact. Life cell imaging with E-cadherin conjugated with Eos fluorescence protein showed that DDR1 stabilizes membrane-bound E-cadherin and the inactivation of Cdc42 mediates DDR1-regulated cell adhesion and differentiation.

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Transforming growth factor-␤1 (TGF-␤1)-induced epithelial-to-mesenchymal transition (EMT) contributes to the pathophysiological development of kidney fibrosis. Although it was reported that TGF-␤1 enhances ␤ 1 integrin levels in NMuMG cells , the detailed molecular mechanisms underlying TGF-␤1-induced ␤ 1 integrin gene expression and the role of ␤ 1 integrin during EMT in the renal system are still unclear. In this study , we examined the role of ␤ 1 integrin in TGF-␤1-induced EMT both in vitro and in vivo. TGF-␤1-induced augmentation of ␤ 1 integrin expression was required for EMT in several epithelial cell lines, and knockdown of Smad3 inhibited TGF-␤1-induced augmentation of ␤ 1 integrin. TGF-␤1 triggered ␤ 1 integrin gene promoter activity as assessed by luciferase activity assay. Both knockdown of Smad3 and mutation of the Smad-binding element to block binding to the ␤ 1 integrin promoter markedly reduced TGF-␤1-induced ␤ 1 integrin promoter activity. Chromatin immunoprecipitation assay showed that TGF-␤1 enhanced Smad3 binding to the ␤ 1 integrin promoter. Furthermore, induction of unilateral ureteral obstruction triggered increases of ␤ 1 integrin in both renal epithelial and interstitial cells. In human kidney with chronic tubulointerstitial fibrosis, we also found a concomitant increase of ␤ 1 integrin and ␣-smooth muscle actin in tubule epithelia. Blockade of ␤ 1 integrin signaling dampened the progression of fibrosis. Taken together, ␤ 1 integrin mediates EMT and subsequent tubulointerstitutial fibrosis, suggesting that inhibition of ␤ 1 integrin is a possible therapeutic target for prevention of renal fibrosis.

Hypoxia inducible factor-1 (HIF-1) is the master transcriptional regulator of the cellular response to altered oxygen levels. HIF-1α protein is elevated in most solid tumors and contributes to poor disease outcome by promoting tumor progression, metastasis, and resistance to chemotherapy. To date, the relationship between HIF-1 and these processes, particularly chemoresistance, has remained largely unexplored. Here, we show that expression of the MAPK-specific phosphatase dual-specificity phosphatase-2 (DUSP2) is markedly reduced or completely absent in many human cancers and that its level of expression inversely correlates with that of HIF-1α and with cancer malignancy. Analysis of human cancer cell lines indicated that HIF-1α inhibited DUSP2 transcription, which resulted in prolonged phosphorylation of ERK and, hence, increased chemoresistance. Knockdown of DUSP2 increased drug resistance under normoxia, while forced expression of DUSP2 abolished hypoxia-induced chemoresistance. Further, reexpression of DUSP2 during cancer progression caused tumor regression and markedly increased drug sensitivity in mice xenografted with human tumor cell lines. Furthermore, a variety of genes involved in drug response, angiogenesis, cell survival, and apoptosis were found to be downregulated by DUSP2. Our results demonstrate that DUSP2 is a key downstream regulator of HIF-1-mediated tumor progression and chemoresistance. DUSP2 therefore may represent a novel drug target of particular relevance in tumors resistant to conventional chemotherapy.

Focal adhesion (FA) assembly, mediated by integrin activation, responds to matrix stiffness; however, the underlying mechanisms are unclear. Here, we showed that β1 integrin and caveolin-1 (Cav1) levels were decreased with declining matrix stiffness. Soft matrix selectively downregulated β1 integrin by endocytosis and subsequent lysosomal degradation. Disruption of lipid rafts with methyl-β-cyclodextrin or nystatin, or knockdown of Cav1 by siRNA decreased cell spreading, FA assembly, and β1 integrin protein levels in cells cultured on stiff matrix. Overexpression of Cav1, particularly the phospho-mimetic mutant Cav1-Y14D, averted soft matrix-induced decreases in β1 integrin protein levels, cell spreading, and FA assembly in NMuMG cells. Interestingly, overexpression of an auto-clustering β1 integrin hindered soft matrix-induced reduction of Cav1 and cell spreading, which suggests a reciprocal regulation between β1 integrin and Cav1. Finally, co-expression of this auto-clustering β1 integrin and Cav1-Y14D synergistically enhanced cell spreading, and FA assembly in HEK293T cells cultured on either stiff ( > G Pa) or soft (0.2 kPa) matrices. Collectively, these results suggest that matrix stiffness governs the expression of β1 integrin and Cav1, which reciprocally control each other, and subsequently determine FA assembly and turnover.

We tested whether cagL amino acid sequence polymorphisms of Helicobacter pylori correlated to clinico-histological outcomes and gastric α5β1 integrin expressions. One hundred forty five patients with H. pylori infection and 47 noninfected controls were enrolled to check gastric integrin α5β1 intensities topographically. The collected isolates were screened for cagL-genotype by polymerase chain reaction (PCR), and assessed for amino acid sequence polymorphisms using sequence translation. Our H. pylori isolates were predominantly (98.6%) cagL-genopositive, 95.8% of which had the RGD motif in their amino acid sequences. The isolates from the gastric cancer (GCA) patients indicated a higher rate of amino acid sequence polymorphisms-Y58 and E59-than those of the non-GCA patients (P < 0.05). The polymorphisms as Y58E59 noted with increased risk of GCA up to 4.6-fold (95%CI: 1.8-11.9). H. pylori-infected patients had higher integrin α5β1 than noninfected patients (P < 0.05). Furthermore, cagL-Y58E59 H. pylori infection predisposed an upward shift in integrin α5β1 (P = 0.007) in the corpus, leading to more severe corpus chronic inflammation (P < 0.05). H. pylori CagL amino acid polymorphisms like Y58E59 correlate with a higher risk of GCA, and may regulate a corpus shift of gastric integrin α5β1 to lead to severe corpus gastritis during gastric carcinogenesis.

Discoidin domain receptors (DDRs) 1 and 2, collagen receptors, regulate cell adhesion and a broad range of cell behavior. Their adhesion-dependent regulation of signaling associated with adhesion proteins has not been elucidated. We report a novel mechanism: the cross talk of DDR1 and E-cadherin negatively and adhesion dependently regulated both DDR1 activity and DDR1-suppressed cell spreading. E-cadherin forms complexes with both DDR1 isoforms (a and b). E-cadherin regulates DDR1 activity associated with the cell-junction complexes formed between DDR1 and E-cadherin. These complexes are formed independently of DDR1 activation and of beta-catenin and p120-catenin binding to E-cadherin; they are ubiquitous in epithelial cells. Small interfering RNA-mediated gene silencing of E-cadherin restores both DDR1 activity and DDR1-suppressed cell spreading and increases the apically and basally located DDR1 in E-cadherin-null cells. We conclude that E-cadherin-mediated adhesions decrease DDR1 activity, which subsequently eliminates DDR1-suppressed cell spreading, by sequestering DDR1 to cell junctions, which prevents its contact with collagen ligand.