Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

AIM: To investigate the implication of the hypoxia inducible factor HIF-1α mRNA in gastric carcinoma and its relation to the expression of vascular endothelial growth factor (VEGF) protein, tumor angiogenesis invasion/metastasis and the patient's survival. METHODS: In situ hybridization was used to examine expression of HIF-1α mRNA, and immunohistochemical staining was used to examine expression of VEGF protein and CD34 in 118 specimens from patients with gastric carcinoma. RESULTS: The positive rates of HIF-1α mRNA and VEGF protein were 49.15% and 55.92%, respectively. Positive expressions of HIF-1α and VEGF in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis were dramatically stronger than stage T1-T2 cases and those without vessel invasion, lymph node metastasis and distant metastasis. The mean microvascular density (MVD) in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis was significantly higher than stage T1-T2 tumors and those without vessel invasion, lymph node metastasis and distant metastasis. The mean MVD in tumors with positive HIF-1α and VEGF expression was significantly higher than that in tumors with negative HIF-1α and VEGF expression. The expression of HIF- 1α was positively correlated with VEGF protein. There were positive correlations between MVD and expressionof HIF-1α and VEGF. The mean survival time and the 5-year survival rate in cases with positive expression HIF-1α and VEGF and MVD value ≥ 41.5/0.72 mm2 were significantly lower than those with negative expression of HIF-1α and VEGF and MVD value < 41.5/0.72 mm2. CONCLUSION: Overexpression of HIF-1α is found in gastric carcinoma. HIF-1α may induce the angiogenesis in gastric carcinoma by upregulating the transcription of VEGF gene, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice.

Relationship between cell adhesion molecules expression and the biological behavior of gastric carcinoma

AIM: To evaluate the relationship between the expression of cell adhesion molecules (CAMs) and the biological behavior of gastric carcinoma. METHODS: Expression of syndecan-1, E-cadherin and integrin β3 were evaluated by immunohistochemical study in a total of 118 gastric carcinomas and 20 non- tumor gastric mucosas. RESULTS: The expressions of syndecan-1 and E-cadherin were significantly lower in gastric carcinoma compared to non-tumor gastric mucosa, and the low expression rates were positively correlated to the tumor invasion depth, vessel invasion, lymph node metastasis and distant metastasis (P < 0.01 in all cases). However, the expression of integrin β3 was significantly higher in gastric carcinoma compared to non-tumor gastric mucosa, and the high expression rates were positively correlated to the tumor invasion depth, vessel invasion, lymph node metastasis and distant metastasis (P < 0.01 in all cases). In addition, the three protein expressions were correlated to the tumor growth pattern (P < 0.01, P < 0.01, and P < 0.05 respectively), but not correlated to tumor differentiation (P > 0.05, P > 0.05 and P > 0.05 respectively). Positive correlation was observed between the expressions of syndecan-1 and E-cadherin, but they which were negatively correlated to the expression of integrin β3 (P < 0.01 in all cases). Univariate analysis demonstrated that the mean survival time and 5-year survival rate were lower in the cases with low expressions of syndecan-1 and E-cadherin and high expression of integrin β3 (P < 0.01, in all cases). COX multivariate analysis showed that the expression level of syndecan-1 could be an independent prognostic index of gastric carcinoma (P < 0.01), whereas E-cadherin and integrin β3 could not be independent indexes (P > 0.05, P > 0.05 respectively). CONCLUSION: The low expression of syndecan-1 and E-cadherin and the high expression of integrin β3 are significantly correlated with the invasion and metastasis of gastric carcinoma, and they are highly correlated with each other. Therefore they may serve as important prognostic markers of gastric carcinoma.

Correlation of integrin β3 mRNA and vascular endothelial growth factor protein expression profiles with the clinicopathological features and prognosis of gastric carcinoma

AIM:To investigate integrin β3 mRNA and vascular endothelial growth factor (VEGF) protein expression in gastric carcinoma, and its correlation with microvascular density, growth-pattern, invasion, metastasis and prognosis. METHODS: In situ hybridization (ISH) of integrin β3 mRNA and immunohistochemistry of VEGF and CD34 protein were performed on samples from 118 patients with gastric cancer. RESULTS: The positive rate of integrin β3 mRNA in non- tumor gastric mucosa (20%) was significantly lower than that of the gastric cancer tissue (52.5%, χ2 = 10.20, P < 0.01). In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the positive expression rates of integrin β3 mRNA were significantly higher than those in patients of expanding type (P < 0.01), stage T1-T2 (P < 0.01), non-vessel invasion (P < 0.01), without lymphatic metastasis (P < 0.01), without hepatic and peritoneal metastasis (P < 0.01), respectively. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic or peritoneal metastasis, the positive expression rates of VEGF protein were significantly higher than those in patients of expanding type (P < 0.01), stage T1-T2 (P < 0.01), non-vessel invasion (P < 0.01), without lymphatic metastasis (P < 0.01), without hepatic and peritoneal metastasis (P < 0.01), respectively. In patients of infiltrating type, stage T3-T4, vessel invasion, lymphatic metastasis, hepatic orperitoneal metastasis, the mean MVD were significantly higher than those in patients of expanding type (P < 0.01), stage T1-T2 (P < 0.01), non-vessel invasion (P < 0.01), without lymphatic metastasis (P < 0.01), without hepatic and peritoneal metastasis (P < 0.01), respectively. It was found that the positive expression rate of integrin β3 mRNA was positively related to that of VEGF protein (P < 0.01) and MVD (P < 0.05), meanwhile the positive expression rate of VEGF protein was positively related to MVD (P < 0.05). The mean survival period in patients with positive expression of integrin β3 mRNA and VEGF, and MVD ≥ 54.9/mm2 was significantly shorter than that in patients with negative expression of integrin β3 mRNA (P < 0.05) and VEGF (P < 0.01), and MVD < 54.9/mm2 (P < 0.01). Five-year survival rate in patients with positive expression of integrin β3 mRNA and VEGF, and MVD ≥ 54.9/mm2 was significantly lower than those with negative expression of integrin β3 mRNA (P < 0.05), VEGF (P < 0.05), and MVD < 54.9/mm2 (P < 0.01). CONCLUSION: Integrin β3 and VEGF expression can synergistically enhance tumor angiogenesis, and may play a crucial role in invasion and metastasis of gastric carcinoma. Therefore, they may be prognostic biomarkers and novel molecular therapeutic targets.

Correlative studies on uPA mRNA and uPAR mRNA expression with vascular endothelial growth factor, microvessel density, progression and survival time of patients with gastric cancer

瞄准：调查在尿激类型 plasminogen 使活跃之物的表示之间的关联(在 A 上面) mRNA，在受体(uPAR ) 上面 mRNA 和蛋白质和临床病理展示的脉管的内皮生长因素(VEGF ) ，微容器密度(MVD ) 和生存时间。方法：原位杂交和免疫组织化学技术被用来学习表情在在 105 个胃的癌标本的 mRNA， uPAR mRNA， VEGF 和 CD34 蛋白质上面。结果：表情在 mRNA， uPAR mRNA 和 VEGF 上面，蛋白质在 61 被观察(58.1%) 案例， 70 (66.7%) 案例并且 67 (63.8%) 案例分别地。起来积极表示在渗入类型情况中评估的 mRNA 和 uPAR mRNA (73.7%，75.4%)，阶段 III-IV (72.1%，75.4%)，容器侵略(63.2%，69.9%)，淋巴的转移(67.1%，74.4%)并且远转移(88.1%，85.7%)比膨胀类型的那些显著地高( chi2 = 15.57 ， P = 0.001 ；chi2 = 6.91， P = 0.046 ) ，阶段 I-II (chi2 = 19.22， P = 0.001；chi2 = 16.75， P = 0.001 ) ，非容器侵略(chi2 = 11.92， P = 0.006；chi2 = 14.15， P = 0.002 ) ，非淋巴的转移(chi2 = 28.41， P = 0.001；chi2 = 22.5， P = 0.005 ) 并且非远的转移(chi2 = 12.32， P = 0.004；chi2 = 17.42， P = 0.002；chi2 = 11.25， P = 0.012；chi2 = 18.12， P = 0.002 ) 。在渗入类型情况(75.4%)中的 VEGF 积极表示率，阶段 III-IV (88.5%)，容器侵略(82.9%)，淋巴的转移(84.3%)和远转移(95.2%)比膨胀类型的那些显著地高( chi2 = 9.61 ， P = 0.021 )，阶段 I-II ( chi2 = 16.66 ， P = 0.001 )，非容器侵略( chi2 = 29.38 ， P = 0.001 )，非淋巴的转移( chi2 = 18.68 ， P = 0.005 )，并且非远的转移( chi2 = 22.72 ， P = 0.007 ；chi2 = 21.62， P = 0.004 ) 。在为积极的标本的吝啬的 MVD 起来 mRNA， uPAR mRNA 和 VEGF 蛋白质比与否定表示组一起的那些显著地高。而且，在 MVD 之间并且在 mRNA 上面的一种积极关系(rs = 0.199， P = 0.042 ) ， uPAR mRNA (rs = 0.278， P = 0.035 ) ，并且 VEGF (rs = 0.398， P = 0.048 ) 表情被观察。在情况与中的吝啬的生存时间在 mRNA， uPAR mRNA 和 VEGF 蛋白质表示或 MVD 价值 】 或 = 上面积极 54.9 是比在有否定表示的情况中的那些显著地短的或 MVD 珍视 【 54.9。结论：在 A 和 uPAR 上面，表情与提高的导致 VEGF 的肿瘤血管生成被相关并且可以在侵略和胃的癌的节的转移起一个作用，胃的癌症的从而服务的同样预示的标记。

Clonality analysis of neuroendocrine cells in gastric adenocarcinoma

AIM:To achieve a better understanding of the origination of neuroendocrine(NE)cells in gastric adenocarcinoma.METHODS:In this study,120 cases of gastric adenocarcinoma were obtained.First,frozen section-immunohistochemistrical samples were selected from a large quantity of neuroendocrine cells.Second,laser capture microdissection was used to get target cells from gastric adenocarcinoma and whole genome amplification was applied to get a large quantity of DNA for further study.Third,genome-wide microsatellite abnormalities[microsatellite instability(MSI),loss of heterozygosity (LOH)]and p53 mutation were detected by polymerase chain reaction(PCR)-single-strand conformation polymer-phism-silver staining and PCR-sequencing in order to identify the clonality of NE cells.RESULTS:The total incidence rate of MSI was 27.4%,while LOH was 17.9%.Ten cases had a highest concordance for the two types of cells.The other samples had similar microsatellite changes,except for cases 7 and10.Concordant p53 mutations exhibited in sample 4,14,21 and 27,and there were different mutations between two kinds of cells in case 7.In case 17,mutation took place only in adenocarcinoma cells.p53 mutation was closely related with degree of differentiation,tumor-node-metastasis stage,vessel invasion and lymph node metastasis.In brief,NE and adenocarcinoma cells showed the same MSI,LOH or p53 mutation in most cases(27/30).In the other three cases,different MSI,LOH or p53 mutation occurred.CONCLUSION:NE and the gastric adenocarcinoma cells may mainly derive from the same stem cells,but the remaining cases showing different origin needs further investigation.