gastrin-releasing-peptide and Stomach-Neoplasms

Gastrin is a pro-proliferative, anti-apoptotic hormone with a central role in acid secretion in the gastric mucosa and a long-standing association with malignant progression in transgenic mouse models. However, its exact role in human gastric malignancy requires further validation. Gastrin expression is tightly regulated by two closely associated hormones, somatostatin and gastrin-releasing peptide, and aspects of their interaction may be deregulated during progression to gastric adenocarcinoma. Furthermore, agonists and antagonists of the receptors for all three hormones have shown modest clinical efficacy against gastric adenocarcinoma, which might provide useful information on the future combined use of these agents.

Topics: Animals; Antineoplastic Agents, Hormonal; Apoptosis; Cancer Vaccines; Cell Differentiation; Cell Movement; Cell Transformation, Neoplastic; Gastrin-Releasing Peptide; Gastrins; Gene Expression Regulation, Neoplastic; Helicobacter Infections; Humans; Mice; Neoplasm Invasiveness; Neoplasms, Experimental; Neovascularization, Pathologic; Precancerous Conditions; Risk Factors; Somatostatin; Stomach Neoplasms

Gastric cancer cells secrete a variety of proangiogenic molecules, including IL-8 and VEGF. However, factors regulating the expression of proangiogenic genes for gastric cancer remain largely undefined. We investigated the role of HGF-induced activation of GRP and Ets-1 transcription factor in expression of the proangiogenic factor IL-8. The genes associated with angiogenesis induced by HGF were screened using cDNA micro-array technology in two gastric cancer cell lines (NUGC-3 and MKN-28). First, GRP RNA and protein were confirmed to be upregulated. Then, expression of GRP, Ets-1, and IL-8 were further estimated by Western blot analysis. A role for Ets-1 in HGF-induced upregulation of IL-8 was determined by knockdown of Ets-1 with Ets-1 sh-RNA and a chromatin immune precipitation assay. The levels of GRP, Ets-1, and IL-8 were upregulated in cells treated with HGF in a dose-dependent manner. HGF-induced expression of Ets-1 and IL-8 was increased more by GRP treatment and inhibited by pretreatment with an ERK 1/2 inhibitor (PD098059). HGF-induced upregulation of IL-8 was repressed by Ets-1 knockdown. HGF enhanced the binding activity of Ets-1 to the IL-8 promoter in control cells, but not in the Ets-1 shRNA cells. We confirmed the functional role of HGF-induced Ets-1 in activation of the IL-8 promoter by the reporter gene assay. Downregulation of IL-8 also decreased in vitro cell invasion. In conclusion, HGF mediated the GRP induction of IL-8 expression through Ets-1, which thus might serve as a promising target for gastric cancer therapy.

Topics: Adenocarcinoma; Base Sequence; Cell Line, Tumor; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Gastrin-Releasing Peptide; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genes, fos; Genes, jun; Genes, Reporter; Hepatocyte Growth Factor; Humans; Interleukin-8; MAP Kinase Signaling System; Molecular Sequence Data; Neoplasm Invasiveness; Neoplasm Proteins; Neovascularization, Pathologic; Promoter Regions, Genetic; Proto-Oncogene Protein c-ets-1; RNA, Small Interfering; Stomach Neoplasms

Gastric cancer is the fourth most common malignancy worldwide. Adenoviral vectors (Ads) have been applied for gene therapy of various cancers because of their high transduction efficiency. However, the infectivity of gastrointestinal cancer cells is poor due to the limited expression of the Coxsackie-adenovirus receptor (CAR). In addition, few tumor-specific promoters (TSPs) have been characterized for this type of cancer. To overcome these problems, we proposed TSP-driven conditionally replicating adenoviruses (CRAds) with fiber modification for virotherapy of gastric cancer.. We assessed the expression profile of eight TSPs in gastric cancer cell lines and evaluated promising candidates in the context of CRAd cytocidal effect. Next, infectivity enhancement by fiber modifications was analyzed in the gastric cancer cell lines. Finally, we combined the TSP-driven CRAds of choice with the fiber modifications to augment the killing effect.. Out of the eight TSPs, the midkine (MK) and cyclooxygenase-2 (Cox-2M and Cox-2L) promoters showed high transcriptional activity in gastric cancer cells. When these promoters were used in a CRAd context, Cox-2 CRAds elicited the strongest cytocidal effect. The greatest infectivity enhancement was observed with adenoviral vectors displaying 5/3 chimeric fibers. Likewise, Cox-2 CRAds with 5/3 chimeric fibers showed the strongest cytocidal effect in gastric cancer cell lines. Therefore, Cox-2 CRAds with 5/3 chimeric fiber modification showed good selectivity and infectivity in gastric cancer cells to yield enhanced oncolysis.. Cox-2 CRAds with 5/3 chimeric fiber modification are promising for virotherapy of gastric cancer.

Topics: Adenoviridae; Cell Line, Tumor; Coxsackie and Adenovirus Receptor-Like Membrane Protein; Cyclooxygenase 2; Cytokines; Enhancer Elements, Genetic; Gastrin-Releasing Peptide; Gastrointestinal Agents; Gene Expression Regulation, Viral; Genetic Vectors; Humans; Integrins; Midkine; Oncolytic Virotherapy; Promoter Regions, Genetic; Proteinase Inhibitory Proteins, Secretory; Proteins; Receptors, Virus; Serine Proteinase Inhibitors; Stomach Neoplasms; Transcription, Genetic; Vascular Endothelial Growth Factor A; Virus Replication

To study the expression of gastrin(GAS) and gastrin releasing peptide(GRP) in patients with gastric cancer and investigate the clinical significance.. The expression of GAS and GRP in sixty patients with gastric cancer was detected by using tissue chip technique and immunohistochemical methods.. The positive rates of GAS and GRP were 30.0% and 11.7% respectively in 60 cases with gastric cancer. The positive rates of GAS and GRP were higher in moderately and poorly differentiated cancers than those in well differentiated cancer (P< 0.05). The positive rates of GAS and GRP were significantly higher in mucinous adenocarcinoma and signet-ring cell carcinoma than those in other types of gastric cancer (P< 0.05). The positive expression of GAS and GRP in gastric cancer was correlated with lymph node metastasis (P< 0.05).. Tissue chip technique is a feasible,rapid,economic and accurate approach for screening clinical tissue specimens on a large scale.

Topics: Adult; Aged; Female; Gastrin-Releasing Peptide; Gastrins; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Protein Array Analysis; Stomach Neoplasms

To establish whether gastrin releasing peptide (GRP) and the GRP receptor (GRPR) are expressed together in gastrointestinal carcinoid tumours.. Twenty six carcinoid tumours from the stomach, small intestine, appendix, and colorectum were investigated by immunohistochemistry for GRP and GRPR.. GRP was detected in nine of 19 tumours and GRPR in 22 of 26. Coexpression of both the ligand and receptor was seen in six of 19 cases. GRPR but not GRP was more strongly expressed in appendix and colonic tumours.. GRP and GRPR are produced by a large number of gastrointestinal carcinoid tumours. An autocrine/paracrine pathway may exist for GRP stimulated cell proliferation in some of these neoplasms, analogous to that seen in small cell anaplastic carcinoma of the lung.

Topics: Appendiceal Neoplasms; Carcinoid Tumor; Colonic Neoplasms; Gastrin-Releasing Peptide; Gastrointestinal Neoplasms; Humans; Neoplasm Proteins; Receptors, Bombesin; Stomach Neoplasms