Wen-Hua Zhan

(-)-Epigallocatechin-3-gallate inhibits VEGF expression induced by IL-6 via Stat3 in gastric cancer

AIM To demonstrate that (-)-Epigallocatechin-3-gallate (EGCG) inhibits vascular endothelial growth factor (VEGF) expression and angiogenesis induced by interleukin-6 (IL-6) via suppressing signal transducer and activator of transcription 3 (Stat3) activity in gastric cancer. METHODS Human gastric cancer (AGS) cells were treated with IL-6 (50 ng/mL) and EGCG at different concentrations. VEGF, total Stat3 and activated Stat3 protein levels in the cell lyses were examined by Western blotting, VEGF protein level in the conditioned medium was measured by enzyme-linked immunosorbent assay, and the level of VEGF mRNA was evaluated by reverse transcription polymerase chain reaction (RT-PCR). Stat3 nuclear translocation was determined by Western blotting with nuclear extract, and Stat3-DNA binding activity was examined with Chromatin immunoprecipitation (ChIP) assay. IL-6 induced endothelial cell proliferation was measured with 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazoliumbromide assay, in vitro angiogenesis was determined with endothelial cell tube formation assay in Matrigel, and IL-6-induced angiogenesis in vitro was measured with Matrigel plug assay. RESULTS There was a basal expression and secretion of VEGF in AGS cells. After stimulation with IL-6, VEGF expression was apparently up-regulated and a 2.4-fold increase was observed. VEGF secretion in the conditioned medium was also increased by 2.8 folds. When treated with EGCG, VEGF expression and secretion were dose-dependently decreased. IL-6 also increased VEGF mRNA expression by 3.1 folds. EGCG treatment suppressed VEGF mRNA expression in a dose-dependent manner. EGCG dose-dependently inhibited Stat3 activation induced by IL-6, but did not change the total Stat3 expression. When treated with EGCG or AG490, VEGF expressions were reduced to the level or an even lower level in the tumor cells not stimulated with IL-6. However, PD98059 and LY294002 did not change VEGF expression induced by IL-6. EGCG inhibited Stat3 nucleus translocation, and Stat3-DNA binding activity was also markedly decreased by EGCG. Furthermore, EGCG inhibited IL-6 induced vascular endothelial cell proliferation and tube formation in vitro and angiogenesis in vitro. CONCLUSION EGCG inhibits IL-6-induced VEGF expression and angiogenesis via suppressing Stat3 activity in gastric cancer, which has provided a novel mechanistic insight into the anti-angiogenic activity of EGCG.

Expression and prognostic impact of PRL-3 in lymph node metastasis of gastric cancer : Its molecular mechanism was investigated using artificial microRNA interference

High PRL‐3 expression had been reported to have close association with lymph node metastasis (LNM) of gastric cancer. However, the prognostic significance of highly expressing PRL‐3 in LNM of human gastric cancer and the role in the metastasis remain unclear. Our study examined PRL‐3 expression both in the LNM (n = 107) and in the primary lesion (n = 137) of gastric cancer, and compared the overall survival rates. RNA interference, induced by recombinant plasmid pcDNA.rPRL3‐miR expressing artificial PRL‐3 miRNA, was employed to knockdown PRL‐3 expression in human SGC7901 gastric cancer cells. Invasion assay and migration assay in vitro were conducted to determine the role of PRL‐3 in the metastasis. The role of PRL‐3 in the proliferation of SGC7901 cells and tumor growth were also determined. We observed that high PRL‐3 expression was more frequently detected in the LNM than in the matched primary lesion (72.9 vs. 47.7%, p < 0.001). Furthermore, the overall survival rate of the patients with high expression of PRL‐3 in the LNM was significantly less than those with moderate/low expression (p = 0.003). Importantly, knockdown of PRL‐3 can significantly reduce both invasion and migration potencies of SGC7901 cells (p < 0.001), and significantly suppressed the proliferation of SGC7901 cells and slowed down the tumor growth (p < 0.001). It was concluded that high expression of PRL‐3 in the LNM had a negative impact on the prognosis of the patients, and plays important roles in LNM of gastric cancer and the tumor growth, which can be a potential therapeutic target and a prognostic factor.

Association of tyrosine PRL-3 phosphatase protein expression with peritoneal metastasis of gastric carcinoma and prognosis.

PurposeIn gastric carcinoma, high expression of PRL-3, a protein tyrosine phosphatase, is associated with lymph node metastasis. We studied the relationship between PRL-3 expression and peritoneal metastasis in gastric carcinoma.MethodsImmunohistochemical analysis using the anti-PRL-3 antibody was done in 639 patients with gastric carcinoma including 89 with peritoneal metastases. We then compared the clinicopathologic characteristics of the PRL-3-positive and PRL-3-negative carcinomas.ResultsPRL-3 was expressed in 70.4% of the primary gastric carcinomas overall; in 80.9% of the cancers with peritoneal metastasis and in 68.7% of those without peritoneal metastasis (P = 0.020). PRL-3 expression was higher in peritoneal metastasis than in the corresponding primary gastric cancers (P = 0.028). PRL-3 expression was correlated with tumor stage (coefficient = 0.343, P = 0.01) and cancer progression, including lymphatic invasion (coefficient = 0.325, P = 0.02), extent of lymph node metastasis (coefficient = 0.322, P = 0.01), and peritoneal metastasis (coefficient = 0.316, P = 0.03). Patients who were PRL-3-negative had a better survival rate than those who were PRL-3-positive at all stages (stage I: log-rank P = 0.046, Wilcoxon P = 0.048; stage II: log-rank P = 0.035, Wilcoxon P = 0.041; stage III: log-rank P = 0.027, Wilcoxon P = 0.033; stage IV: log-rank P = 0.032, Wilcoxon P = 0.030).ConclusionsPeritoneal metastasis appears to be correlated with PRL-3 expression, tumor stage, lymphatic invasion, and extent of lymph node metastasis. PRL-3 expression was negatively correlated with prognosis in patients with gastric cancer.

Spleen Preservation in Radical Surgery for Gastric Cardia Cancer

BackgroundIn gastric cardia cancer (GCC), the spleen is usually removed when the tumor is resected. This allows thorough lymph node dissection in the splenic hilus. However, the long-term effect of splenectomy on patient survival is controversial. The purpose of this study was to investigate the effect of spleen preservation on survival following radical resection for gastric cardia cancer.MethodsWe reviewed the records of 116 GCC patients (Siewert types II and III) who underwent radical resection with D2 or D3 lymphadenectomy between July 1994 and December 2003. Survival status was ascertained in December 2004 and data from 108 patients were analysed. Of these 108 patients, 38 underwent splenectomy and 70 had splenic preservation. Clinicopathological features and prognostic data of the splenectomy(+) and splenectomy(−) groups were compared.ResultsSeventy-four patients (68.5%) had lymph node involvement; 18 (16.7%) had involvement of nodes in the splenic hilus. Postoperative morbidity in the two groups was similar. Overall 5-year survival was higher in the splenectomy(−) group than the splenectomy(+) group (38.7% versus 16.9%, P =.008). Multivariate regression indicated that tumor invasion (P =.009) and lymph node metastasis (P = .001) were independent prognostic factors – they predicted decreased survival – with or without splenectomy. Although splenectomy was be associated with lower survival, it was not an independent prognostic factor (P =.085).ConclusionsSplenectomy does not improve survival of patients who undergo curative resection for gastric cardia cancer. Thus, the spleen should be preserved in patients without direct cancer invasion of the spleen.

The effect of the expression of vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 on the clinical outcome in patients with gastric carcinoma

AIMS We aimed to investigate the relationship among VEGF-C/VEGFR-3 expression, lymphatic metastasis and patient prognosis in gastric carcinoma. MATERIAL AND METHODS VEGF-C and VEGFR-3 expression in gastric carcinoma tissues obtained from 204 patients who underwent curative gastrectomy (105 cases presented with lymph node metastasis and 99 cases without metastasis) was examined immunohistochemically. There was no significant difference in the other clinicopathologic variables except for postoperative pathological tumor stage (pT) and TNM stage between the two groups. The results were statistically processed. RESULTS The results showed that VEGF-C was located mainly in the cytoplasm of tumor cells and VEGFR-3 was found predominantly in the endothelium of lymphatic vessels. VEGF-C and VEGFR-3 expression was more frequent in gastric carcinoma tissues than that in normal gastric tissues, 54.90% and 35.29% respectively, which revealed that the expression of VEGF-C and VEGFR-3 was significantly stronger in patients with lymph node metastasis than in those without metastasis. Patients who had positive staining for VEGF-C showed significantly less favorable survival rates compared with patients who had negative staining for VEGF-C. The survival rates of patients who had positive staining for VEGFR-3 also were significantly lower compared with patients who had negative staining for VEGFR-3. Patients who had positive staining for both VEGF-C and VEGFR-3 exhibited the most unfavorable prognosis. Multivariate analysis demonstrated that the expression of VEGF-C and VEGFR-3 was an independent prognostic determinant. In addition, faint to moderate VEGF-C expression was detected in normal gastric epithelial cells (18/204, 8.9%). CONCLUSIONS VEGF-C and VEGFR-3 expression could serve as a prognostic biomarker in patients with gastric carcinoma.

Lymphatic endothelial cell-secreted CXCL1 stimulates lymphangiogenesis and metastasis of gastric cancer.

Lymph node metastasis is a significant factor in gastric cancer prognosis. It is well known that cancer cells secrete lymphangiogenic factors, thereby promoting lymphangiogenesis. However, the effects of lymphatic endothelial cell (LEC)‐secreted factors on the process of lymphangiogenesis and tumor cell metastasis remain unclear. We established an animal model and successfully isolated LECs from afferent lymph vessels of sentinel lymph nodes (SLNs) in animal models. A microarray analysis was performed to characterize gene expression profile in afferent LECs induced by metastatic cancer cells. There were significant differences in 846 genes between normal LECs and LECs with lymph node metastasis. Among these genes, we found that expression of CXCL1 was upregulated, which was confirmed by quantitative reverse‐transcriptase polymerase chain reaction. In a coculture system, gastric cancer cells induced CXCL1 secretion from LECs, which was associated with the NF‐κB pathway. CXCL1 stimulated LECs migration and tube formation involving FAK‐ERK1/2‐RhoA activation and reorganization of F‐actin. In human gastric cancer specimens, CXCR2 expression was positively correlated with TNM (Tumor, node, metastasis) stage and lymphatic vessel density. These results suggested that LECs of afferent SLNs had specific expression profiles, which were distinct from those of normal lymphatic vessels and appeared to promote metastasis. The expression pattern described in our study, including CXCL1 in LECs and its receptor CXCR2 in cancer cells, offers a promising therapeutic target for gastric cancer.

Is albumin administration beneficial in early stage of postoperative hypoalbuminemia following gastrointestinal surgery?: a prospective randomized controlled trial

BACKGROUND Surgeons commonly see postoperative hypoalbuminemia, but whether exogenous albumin administration is beneficial for these patients is unclear. METHODS A prospective, randomized study design was used, allocating 127 hypoalbuminemic patients into the albumin or saline group after gastrointestinal surgery. We investigated the development of postoperative hypoalbuminemia, nutritional status, postoperative fluid balance, postoperative complications, and postoperative hospital stay. RESULTS Plasma albumin concentrations of both groups decreased after operations (P <.01). No significant differences were found between groups (P >.05) in changes in postoperative plasma albumin concentration from baseline levels. Postoperative plasma albumin, total protein, and prealbumin levels were similar in the 2 groups. While 3-day and 5-day recovery ratios were similar, 7-day recovery ratios were lower in the albumin group (P <.05). No significant difference was found in overall fluid administration, urine output, or the incidence of postoperative complications between groups (23.4% for albumin group and 12.7% for control group, P = .116). CONCLUSIONS Albumin administration in the early stage of postoperative hypoalbuminemia following gastrointestinal surgery is not beneficial in correcting hypoalbuminemia or in clinical outcomes.

Clinical features and risk factors for primary surgery in 205 patients with Crohn's disease: analysis of a South China cohort.

BACKGROUND: The frequency of Crohns disease in China is increasing, but few reports are available on clinical features, phenotypes according to the Montreal classification, or risk factors for surgery in mainland China. OBJECTIVE: This study aimed to assess clinical presentation, phenotypes according to the Montreal classification, and potential risk factors for initial surgery in patients with Crohns disease in southern China. DESIGN: This was an observational study designed as a retrospective analysis of a historical cohort. SETTINGS: The study was conducted at a tertiary referral hospital, Guangzhou, China. PATIENTS: Medical records of 212 consecutive patients with Crohns disease were reviewed; data from 205 patients who met inclusion criteria were analyzed. MAIN OUTCOME MEASURES: The value of age, location, and behavior of disease according to the Montreal system, smoking behavior, and other clinical variables as potential risk factors in predicting the requirement for initial surgery was assessed by use of Cox regression analysis. RESULTS: A total of 205 patients were studied. Abdominal pain (181 patients, 88.3%) was the most common clinical presentation. At the time of diagnosis, age was between 17 and 40 years in 145 patients (70.7%). The Montreal classification of disease location was L3 (ileocolonic) in 114 patients (55.6%), disease behavior was classified as inflammatory in 133 patients (64.9%). During the course of their disease (median, 4 years; range, 1–21 years), 79 patients (38.5%) required bowel resection. Kaplan-Meier analysis showed that the overall cumulative rate of primary bowel surgery was 17.6% at 1 year after onset of symptoms, 20.3% at 2 years, 35.2% at 5 years, and 58.3% at 10 years. In our final Cox model, stricturing (HR, 3.67; 95% CI, 2.14–6.29; P < .001), penetrating behavior (HR, 4.60; 95% CI, 2.58–8.22; P < .001), and smoking habit (HR, 2.02; 95% CI, 1.15–3.53; P = .014) were significantly associated with an increased risk for bowel resection. LIMITATIONS: The study was limited by its retrospective nature. CONCLUSIONS: In Chinese patients with Crohns disease, abdominal pain is the most common clinical presentation, and the most common phenotypes are age 17 to 40 years at diagnosis, ileocolonic disease location, and inflammatory disease behavior. More than one-third of patients require surgery at a median of 4 years after onset of symptoms. Stricturing, penetrating disease, and smoking are associated with an increased risk of requiring bowel resection.

Double-positive expression of high-mobility group box 1 and vascular endothelial growth factor C indicates a poorer prognosis in gastric cancer patients

BackgroundAlthough many studies have indicated that high-mobility group box 1 protein (HMGB1) is associated with oncogenesis and a worse prognosis, the prognostic value of HMGB1 in gastric cancer (GC) remains unclear. In the present work, we aimed to evaluate the role of HMGB1 in GC and examined whether aberrant expression of both HMGB1 and vascular endothelial growth factor C (VEGF-C) increased the malignant potential of GC.MethodsA total of 166 GC patients and 32 normal subjects were enrolled. HMGB1 and VEGF-C expression was detected by tissue microarrays (TMAs) and immunohistochemical staining. The correlation between HMGB1 and VEGF-C expression and their relationships with clinicopathological GC variables were examined. Univariate and multivariate analyses were performed using the Cox proportional hazard model to predict the factors related to the patients‘ overall survival rates.ResultsHMGB1 and VEGF-C expression were observed in 81 (48.80%) and 88 (53.01%) tumors, respectively, significantly higher than the rates among the corresponding controls. In addition, HMGB1 and VEGF-C expression were positively correlated (R2 = 0.972). HMGB1 expression was also closely associated with tumor size, pT stage, nodal status, metastasis status, TNM stage, and poor prognosis. Multivariate survival analysis indicated that patients with HMGB1 and VEGF-C coexpression had the worst prognoses and survival rates (hazard ratio, 2.78; log rank P<0.001).ConclusionsHMGB1 is commonly expressed in GC. Combined evaluation of HMGB1 and VEGF-C may serve as a valuable independent prognostic factor for GC patients.

Use of absorbable hemostatic gauze with medical adhesive is effective for achieving hemostasis in presacral hemorrhage

BACKGROUND Management of presacral hemorrhage is always challenging. Herein we describe the use of an absorbable hemostatic gauze with α-cyanoacrylate medical adhesive to achieve hemostasis. METHODS In this study, we conducted total mesorectal excision for the treatment of rectal cancer in 258 patients from March 2006 to May 2009. Intraoperative presacral hemorrhage developed in 5 (2%) patients during rectal mobilization. RESULTS In these 5 patients, massive bleeding could not be controlled by pressure and pelvic packing with gauze. An absorbable hemostatic gauze spread with medical adhesive was compressed onto the bleeding vessel for at least 20 minutes. Hemostasis was achieved successfully and was maintained during the surgery. Patients recovered uneventfully and no postoperative events were noted. CONCLUSIONS The use of an absorbable hemostatic gauze with medical adhesive is a simple and effective method for achieving hemostasis when massive presacral hemorrhage occurs. However, its effectiveness needs to be confirmed in a controlled study in a properly selected patient population.