Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Overexpression of epidermal growth factor (EGF) and urokinase plasminogen activator receptor (uPAR) have been observed in human gastric cancers. However, the interaction between EGF and uPAR in gastric cancer has not been well elucidated. In this study, we investigated the effect of EGF on uPAR expression and the underlying signal pathways in human gastric cancer AGS cells. EGF induced uPAR mRNA expression in a time- and concentration-dependent manner. EGF also induced uPAR promoter activity. In addition, EGF induced the activation of extracellular signal regulated kinase-1/2 (ERK-1/2) and P38 mitogen-activated protein kinase (MAPK) but not the activation of c-Jun amino terminal kinase. A specific inhibitor of MEK-1 (an upstream effector of ERK-1/2) and a dominant negative MEK-1 were able to suppress the EGF-induced uPAR promoter activity. Site-directed mutagenesis and electrophoretic mobility shift assays demonstrated that the binding sites of transcription factors, activator protein-1 (AP-1) and nuclear factor (NF)-kappaB, are involved in the EGF-induced uPAR transcription. Suppression of the EGF-induced uPAR promoter activity by the AP-1 decoy oligonuclotide, as well as expression vectors encoding mutated-type NF-kappaB-inducting kinase and I-kappaB, confirmed that the activation of AP-1 and NF-kappaB are essential for the EGF-induced uPAR upregulation. The AGS cells pretreated with EGF showed a remarkably enhanced invasiveness and this effect was partially abrogated by uPAR neutralizing antibodies and by the inhibitors of ERK-1/2, AP-1, and NF-kappaB. The above results suggest that EGF induces uPAR expression via ERK-1/2, AP-1, and NF-kappaB signaling pathways and, in turn, stimulates cell invasiveness in human gastric cancer AGS cells.
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PMID:EGF stimulates uPAR expression and cell invasiveness through ERK, AP-1, and NF-kappaB signaling in human gastric carcinoma cells. 1902 Jul 43

Cathepsin X (CTSX) is strongly up-regulated in Helicobacter pylori-infected gastric mucosa and intestinal-type gastric cancer. The overexpression of CTSX is mediated predominantly by associated macrophages; depends on a functional type IV-secretion system; and leads to increased migration of gastric epithelial cells. In the present study, we analysed the role of CagA in CTSX overexpression and identified H. pylori-induced inflammatory factors and signalling pathways required for stimulating CTSX expression by H. pylori. Gastric epithelial cells were co-cultured with macrophages in Transwell chambers of 0.4 microm pore size, enabling exchange of fluids but retracting H. pylori. N87 gastric epithelial cells were infected with H. pylori P1 wild-type strain in the presence of inhibitors for p38, JNK, and ERK1/2 signal transduction pathways. Furthermore, cytokines and growth factors were tested for their regulatory function using inhibitory antibodies, and their gene expression was studied by quantitative RT-PCRs and western blots. CTSX is strongly up-regulated at both the mRNA and the protein levels by TNF-alpha, IL-1beta, IL-6, and IL-8, depending on cell type. All these cytokines were found to be increased by five- to ten-fold in macrophages by H. pylori infection of co-cultured N87 gastric epithelial cells. In macrophages, H. pylori up-regulated CTSX via ERK1/2 signalling pathways, and in N87 cells via JNK irrespective of p38 signalling. Our results suggest that H. pylori induced overexpression of CTSX in macrophages and epithelium through specific cytokines that are initiated by CagA-dependent pathways in a cell type-dependent manner.
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PMID:Regulation of cathepsin X overexpression in H. pylori-infected gastric epithelial cells and macrophages. 1909 Apr 85

Midkine (MDK), a heparin-binding growth factor, modulates the proliferation and migration of various cells, is often highly expressed in many malignant tumors, and may act as an oncoprotein. We found that MDK is overexpressed in clinical human gastric cancer tissues relative to its expression in adjacent noncancerous tissues. To further investigate the biological activities of MDK in gastric cancer, we introduced the MDK gene into human SGC7901 gastric cancer cells, where it contributed to the proliferation of SGC7901 cells in vitro and in vivo. Conversely, the knockdown of MDK expression by siRNA resulted in significantly reduced proliferation of BGC823 cells. Our study also shows that MDK activates both the Akt and ERK1/2 pathways and upregulates the expression of several cell-cycle-related proteins, including cyclin A, cyclin D1, Cdk2, Cdk4, and Cdk6, which in part explains the contribution of MDK to gastric cancer cell survival and growth. These results demonstrate that MDK contributes to gastric cancer cell proliferation and suggest that it plays an important role in the development of human gastric cancer.
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PMID:Midkine positively regulates the proliferation of human gastric cancer cells. 1925 Jul 38

Angiotensin II is a main effector peptide in renin-angiotensin system, acting as a growth promoter via angiotensin II type 1 (AT1) receptor. The present study examined intrinsic angiotensin II generating system in gastric cancer and potential roles of angiotensin II in cellular proliferation and survival. The expression of AT1 receptor was examined in gastric cancer cell lines and tissues. In addition, we measured angiotensin II concentration in tissues from twenty gastric cancer and corresponding normal region using the florisil method. In vitro, we investigated the potential roles of angiotensin II in cellular proliferation and cell survival in cultured human gastric cancer cell line. The effects of AT1 receptor blocker candesartan were evaluated in a mouse model of peritoneal carcinomatosis. AT1 receptor protein was expressed in gastric cancer cell lines and tissues. Angiotensin II concentration in tumor region (1447+/-624 pg/g wet) was significantly higher than those of normal region (775+/-320 pg/g wet) (p<0.05). Angiotensin II stimulates the cell proliferation in the AT1 receptor-positive OCUM2MD3 gastric cancer cell line and this proliferative effect of angiotensin II was inhibited by a specific AT1 receptor antagonist, candesartan. We also confirmed the angiotensin II stimulated ERK1/2, nuclear transcript factor-kappaB (NF-kappaB) and surviving activation, which are central molecules of cellular proliferation and survival in OCUM2MD3 cells. Candesartan significantly prolonged survival time in a mouse model of peritoneal carcinomatosis compared with control group (p=0.0.197, log-rank test). Our data provide in vivo evidence of intrinsic angiotensin II generating system in gastric cancer and indicate locally formed angiotensin II is involved in cellular proliferation and survival.
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PMID:Local angiotensin II-generation in human gastric cancer: correlation with tumor progression through the activation of ERK1/2, NF-kappaB and survivin. 1942 75

The MDM2 proto-oncogene is overexpressed in many human tumors. Although MDM2 inhibits tumor-suppressor function of p53, there exists a p53-independent role for MDM2 in tumorigenesis. Therefore, downregulation of MDM2 has been considered an attractive therapeutic strategy. Hispolon extracted from Phellinus species was found to induce epidermoid and gastric cancer cell apoptosis. However, the mechanisms are not fully understood. Herein, we report our findings that hispolon inhibited breast and bladder cancer cell growth, regardless of p53 status. Furthermore, p21(WAF1), a cyclin-dependent kinase inhibitor, was elevated in hispolon-treated cells. MDM2, a negative regulator of p21(WAF1), was ubiquitinated and degraded after hispolon treatment. We also found that activated ERK1/2 (extracellular signal-regulated kinase1/2) was recruited to MDM2 and involved in mediating MDM2 ubiquitination. Based on this finding, we investigated whether the sensitivity of cells to hispolon was related to ERK1/2 activity. The results indicated that cells with higher ERK1/2 activity were more sensitive to hispolon. In addition, hispolon-induced caspase-7 cleavage was inhibited by the ERK1/2 inhibitor, U0126. In conclusion, hispolon ubiquitinates and downregulates MDM2 via MDM2-recruited activated ERK1/2. Therefore, hispolon may be a potential anti-tumor agent in breast and bladder cancers.
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PMID:Hispolon from Phellinus linteus has antiproliferative effects via MDM2-recruited ERK1/2 activity in breast and bladder cancer cells. 1947 14

We have previously reported the synergistic cytotoxic effects of Docetaxel (TXT) and S-1 in gastric cancer in vitro and in vivo, and the combination regimen is now under phase III clinical trail. In this study, to elucidate whether the rapamycin, the inhibitor of the mTOR (mammalian target of rapamaycin), can enhance the potentiation of TXT and 5-fluorouracil (5-Fu) in gastric carcinoma cells. Rapamycin inhibited the growth of TMK-1, MKN-28, MKN-45 and MKN-74 cell lines by MTT assay, and it demonstrated the cytostatic effects as G1 arrest shown by flowcytometry. However, the cytotoxic effects of 5-Fu, TXT and cisplatin were enhanced by 2 to 4 times with the concomitant administration of rapamycin. To clarify the mechanism of the potentiation, the expression changes of the enzymes relating DNA metabolism and cell growth signal transduction pathways were examined by western blot analysis. Interestingly, the expression of thymidilate synthase was markedly decreased by the administration of rapamycin in TMK-1 cells in a time- and dose-dependent manner. Moreover, rapamycin decreased the phosphorylation of 4E-BP1, the phosphorylation of ERK1/2 and enhanced the phosphorylation of c-Jun NH2-terminal kinase, and the activation of caspase of apoptotic pathways in combination with TXT. These results strongly indicate that the mTOR inhibitor can enhance the potentiation of TXT and 5-Fu or S-1 and can serve as a new therapeutic tool for advanced and recurrent gastric cancer patients.
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PMID:Rapamycin enhances chemotherapy-induced cytotoxicity by inhibiting the expressions of TS and ERK in gastric cancer cells. 1985 12

The Helicobacter pylori protein CagA may undergo tyrosine phosphorylation following its entry into human gastric epithelial cells with downstream effects on signal transduction. Disruption of the gp130 receptor that modulates the balance of the SHP2/ERK and JAK/STAT pathways enhanced peptic ulceration and gastric cancer in gp130 knock-out mice. In this study, we evaluated the effect of translocated CagA in relation to its tyrosine phosphorylation status on the gp130-mediated signal switch between the SHP2/ERK and JAK/STAT3 pathways. We showed that in the presence of CagA, SHP2 was recruited to gp130. Phosphorylated CagA showed enhanced SHP2 binding activity and ERK1/2 phosphorylation, whereas unphosphorylated CagA showed preferential STAT3 activation. These findings indicate that the phosphorylation status of CagA affects the signal switch between the SHP2/ERK and JAK/STAT3 pathways through gp130, providing a novel mechanism to explain H. pylori signaling.
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PMID:Helicobacter pylori CagA phosphorylation status determines the gp130-activated SHP2/ERK and JAK/STAT signal transduction pathways in gastric epithelial cells. 2034 91

Hypoxia is recognized as an important factor contributing to cancer development and drug resistance. Cetuximab, a chimeric monoclonal antibody to EGFR, is known to inhibit HIF-1 alpha expression levels and to enhance the cytotoxicity of chemotherapeutic agents. We demonstrated that hypoxia induced drug resistance in gastric cancer cells. Cetuximab enhanced oxaliplatin-induced cytotoxicity and apoptosis in normoxia and caused a reversal of drug resistance in hypoxia. Normoxic and hypoxic gastric cancer cells were treated with cetuximab, oxaliplatin or the combination and assessed for cell growth, proliferation, and apoptosis. Combination treatment resulted in a marked inhibition of HIF-1 alpha expression levels in hypoxic cells and caused a significant reduction in the expression of activated phosphorylated AKT, ERK1/2, p-BAD and VEGF in both normoxia and hypoxia with greater levels of inhibition in hypoxia. In summary, cetuximab inhibits HIF-1 alpha expression via the MAPK/ERK and PI3K/AKT signaling pathways and functions to overcome drug resistance induced by hypoxia. Cetuximab-oxaliplatin combination therapy may therefore emerge as an attractive treatment strategy for advanced gastric cancer.
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PMID:Cetuximab enhances the effect of oxaliplatin on hypoxic gastric cancer cell lines. 2042 33

Hypoxia is a common characteristic feature of solid tumors, and carcinoma cells are known to secrete many growth factors. These growth factors, such as vascular endothelial growth factor (VEGF), play a major role in the regulation of tumor angiogenesis and metastasis. In this study, the effect of gamma-tocotrienol, a natural product commonly found in palm oil and rice bran, on the accumulation of HIF-1alpha protein and the paracrine secretion of VEGF in human gastric adenocarcinoma SGC-7901 cell line induced by cobalt(II) chloride (as a hypoxia mimic) was investigated. These results showed that cobalt(II) chloride induced the high expression of VEGF in SGC-7901 cells at dose of 150 micromol/L for 24h. Both basal level and cobalt(II) chloride-induced HIF-1alpha protein accumulation and VEGF paracrine secretion were inhibited in SGC-7901 cells treated with gamma-tocotrienol at 60 micromol/L treatment for 24 h. U0126, a MEK1/2 inhibitor, decreased the expression of HIF-1alpha protein and the paracrine secretion of VEGF under normoxic and hypoxic conditions. In this study, gamma-tocotrienol also significantly inhibited the hypoxia-stimulated expression of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2). The mechanism seems to involve in inhibiting hypoxia-mediated activation of p-ERK1/2, it leads to a marked decrease in hypoxia-induced HIF-1alpha protein accumulation and VEGF secretion. These data suggest that HIF-1alpha/VEGF could be a promising target for gamma-tocotrienol in an effective method of chemoprevention and chemotherapy in human gastric cancer.
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PMID:gamma-Tocotrienol modulates the paracrine secretion of VEGF induced by cobalt(II) chloride via ERK signaling pathway in gastric adenocarcinoma SGC-7901 cell line. 2045 89

Helicobacter pylori (H. pylori) is a major human pathogen and plays a central role in chronic gastritis and gastric cancer. Since the adhesion of H. pylori to the human gastric epithelium is the initial and critical step of its infection, anti-H. pylori adhesion agents may be effective for the prevention and therapy of H. pylori-associated diseases. CD74 has recently been identified as a new receptor for H. pylori urease, and we have previously reported that several citrus components strongly suppressed CD74 expression in NCI-N87 gastric carcinoma cells. We found in this present study that auraptene (citrus coumarin) disrupted serum starvation-induced extracellular signaling-regulated kinase (ERK) 1/2 activation and attenuated H. pylori adhesion and IL-8 production in a co-culture system. In addition, the knockdown of CD74 expression led to a significant decrease of H. pylori adhesion, but unexpectedly increased IL-8 production. However, PD98059 (a MEK1/2 inhibitor) dramatically down-regulated this cytokine, suggesting MEK/ERK-dependent IL-8 production. Our results suggest that auraptene suppressed H. pylori adhesion and resulting chemokine production by disrupting ERK1/2 activation.
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PMID:Suppression of CD74 expression and Helicobacter pylori adhesion by auraptene targeting serum starvation-activated ERK1/2 in NCI-N87 gastric carcinoma cells. 2046 Jul 32


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