Identification of anti-gastric cancer effects and molecular mechanisms of resveratrol: From network pharmacology and bioinformatics to experimental validation.

BACKGROUND: Gastric cancer (GC) is one of the most aggressive malignancies with limited therapeutic options and a poor prognosis. Resveratrol, a non-flavonoid polyphenolic compound found in a variety of Chinese medicinal materials, has shown excellent anti-GC effect. However, its exact mechanisms of action in GC have not been clarified. AIM: To identify the effects of resveratrol on GC progression and explore the related molecular mechanisms. METHODS: Action targets of resveratrol and GC-related targets were screened from public databases. The overlapping targets between the two were confirmed using a Venn diagram, and a "Resveratrol-Target-GC" network was constructed using Cytoscape software version 3.9.1. The protein-protein interaction (PPI) network was constructed using STRING database and core targets were identified by PPI network analysis. The Database for Annotation, Visualization and Integrated Discovery database was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. A "Target-Pathway" network was created by using Cytoscape 3.9.1. The RNA and protein expression levels of core target genes were observed using the Cancer Genome Atlas and the Human Protein Atlas databases. DriverDBv3 and Timer2.0 databases were used for survival and immune infiltration analysis. Subsequently, the findings were further verified by molecular docking technology and in vitro experiments. RESULTS: A total of 378 resveratrol action targets and 2154 GC disease targets were obtained from public databases, and 181 intersection targets between the two were screened by Venn diagram. The top 20 core targets were identified by PPI network analysis of the overlapping targets. GO function analysis mainly involved protein binding, identical protein binding, cytoplasm, nucleus, negative regulation of apoptotic process and response to xenobiotic stimulus. KEGG enrichment analysis suggested that the involved signaling pathways mainly included PI3K-AKT signaling pathway, MAPK signaling pathway, IL-17 signaling pathway, TNF signaling pathway, ErbB signaling pathway, etc. FBJ murine osteosarcoma viral oncogene homolog (FOS) and matrix metallopeptidase 9 (MMP9) were selected by differential expression analysis, and they were closely associated with immune infiltration. Molecular docking results showed that resveratrol docked well with these two targets. Resveratrol treatment arrested the cell cycle at the S phase, induced apoptosis, and weakened viability, migration and invasion in a dose-dependent manner. Furthermore, resveratrol could exhibit anti-GC effect by regulating FOS and MMP9 expression. CONCLUSION: The anti-GC effects of resveratrol are related to the inhibition of cell proliferation, migration, invasion and induction of cell cycle arrest and apoptosis by targeting FOS and MMP9.

Application of Transumbilical Laparoscopic Surgery on Low/Ultralow Rectal Cancer for Anal Sphincter Preservation.

Background: Rectal cancer is a common malignant tumor in the gastrointestinal tract. This work compares the effects of transumbilical laparoscopic surgery (TULS) and laparoscopic-assisted surgery on the anus-preserving effect of low/ultralow rectal cancer. Materials and Methods: Eighty patients with rectal cancer admitted to our hospital from February 2011 to July 2016 were randomly selected and divided into the laparoscopic group and TULS group, 40 cases in each group, all underwent radical anorectal cancer radical surgery. Statistical analysis was performed on surgical-related indicators in the two groups. Results: Two patients converted to open surgery were excluded. Five patients were excluded because of radical abdomen perineal resection for rectal cancer. Six patients were converted to TULS from laparoscopic surgery. Sixty-seven patients in the experimental group successfully completed anus-sparing surgery, and none died during the operation. The compliance rate of the distance between the lower edge of the tumor and the incision edge of the specimen in the TULS group was better than that in the laparoscopic group (P < .05). There were no significant differences between the two groups in terms of surgical time, blood loss, number of lymph node dissections, functional time of voluntary defecation and postoperative complications, tumor-free recurrence rate at 3 years, and 3-year survival rate after surgery (P > .05). Conclusions: The TULS method is safe and feasible in low and ultralow rectal cancer surgery. It has more advantages than laparoscopic-assisted surgery for anus preservation.

Comparative analysis of laparoscopic proximal gastrectomy plus semi-embedded valve anastomosis with laparoscopic total gastrectomy for adenocarcinoma of the esophagogastric junction: a single-center retrospective cohort study.

BACKGROUND: We invented a new antireflux anastomosis method for use in proximal gastrectomy for adenocarcinoma of the esophagogastric junction (AEG) and named it semi-embedded valve anastomosis (SEV). This study was conducted to compare and analyze the short-term efficacy and long-term prognosis of this anastomosis reconstruction method versus laparoscopic total gastrectomy (LTG). METHODS: We retrospectively analyzed the general data and surgical outcomes of patients with AEG who underwent three united laparoscopic proximal gastrectomy plus semi-embedded valve anastomosis (TULPG-SEV, N = 20) and LTG (N = 20) at our hospital from January 2015 to September 2017 and investigated the incidence of postoperative reflux esophagitis and postoperative nutritional status between the two groups. Survival analysis was also performed. RESULTS: The operative time (178.25 ± 15.41 vs 196.5 ± 21.16 min) and the gastrointestinal reconstruction time (19.3 ± 2.53 vs 34.65 ± 4.88 min) of the TULPG-SEV group were significantly less than that of the LTG group. There was no difference in intraoperative blood loss, length of hospital stay, and postoperative complications. There was no difference in the scores on the postoperative reflux disease questionnaires (RDQs) conducted 1 month (P = 0.501), 3 months (P = 0.238), and 6 months (P = 0.655) after surgery between the TULPG-SEV group and LTG group. Gastroscopy revealed 2 cases of reflux esophagitis (grade B or higher) in each group. The postoperative hemoglobin level was better in the TULPG-SEV group than in the LTG group, and the difference was most noticeable at 1 month after surgery (P = 0.024) and 3 months after surgery (P = 0.029). The levels of albumin and total protein were not significantly different between the groups. There were more patients with weight loss over 5 kg after surgery in the LTG group than in the TULPG-SEV group (P = 0.043). There was no significant difference in the 3-year overall survival rate between the two groups (P = 0.356). CONCLUSION: SEV has a certain antireflux effect and can reduce the anastomosis time. Proximal gastrectomy may be better than total gastrectomy for maintaining postoperative hemoglobin levels and reducing weight loss.

Semi-embedded valve anastomosis a new anti-reflux anastomotic method after proximal gastrectomy for adenocarcinoma of the oesophagogastric junction.

BACKGROUND: There is a high probability of gastroesophageal reflux after laparoscopic proximal gastrectomy for adenocarcinoma of the oesophagogastric junction (AEG). Various anti-reflux anastomotic methods are emerging in clinical practice; however, none of them have been widely accepted. We have innovated a new type of anti-reflux anastomotic method, named semi-embedded valve anastomosis. The aim of this study was to explore the feasibility and anti-reflux effect of the new anastomotic method. METHODS: The clinical data of 28 patients with Siewert II AEG who were treated by semi-embedded valve anastomosis were collected. The key point of the operation is to reconstruct a simulated valve and form an anti-reflux barrier similar to the physiological mechanism. The gastroesophageal reflux disease questionnaire (GerdQ) and classification of gastroesophageal reflux under electron microscopy were used to evaluate gastroesophageal reflux after the operation. RESULTS: The mean operative duration was 164.3 ± 19.0 min, the median intraoperative haemorrhage volume was 65 ml, the average number of lymph nodes dissected was 23 ± 2.6, the time for valve construction was 15.8 ± 3.2 min, the time for anastomotic reconstruction was 35.4 ± 4.8 min, the median time to first flatus was 3 d, and the median hospitalization duration was 12 d. There was one case of postoperative anastomotic stenosis. The GerdQ score [median (range)] was as follows: 2 (0-6), preoperation; 0 (0-8), 1 month postoperation; 2 (0-12), 3 months postoperation; and 3 (0-12), 6 months postoperation. The Wilcoxon signed-rank sum test was carried out at different times after the operation and the day before the operation, and the differences were not significant. There was one case of grade B gastroesophageal reflux according to the Los Angeles classification system among the gastrofibroscopic re-examination reports of 28 cases. CONCLUSION: Semi-embedded valve anastomosis is safe and feasible after proximal gastrectomy for Siewert II AEG and has good anti-reflux effects.

Inhibitory effects of CP on the growth of human gastric adenocarcinoma BGC-823 tumours in nude mice.

Objective To investigate the potential antitumour effects of [2-(6-amino-purine-9-yl)-1-hydroxy-phosphine acyl ethyl] phosphonic acid (CP) against gastric adenocarcinoma. Methods Human BGC-823 xenotransplants were established in nude mice. Animals were randomly divided into control and CP groups, which were administered NaHCO3 vehicle alone or CP dissolved in NaHCO3 (200 µg/kg body weight) daily, respectively. Tumour volume was measured weekly for 6 weeks. Resected tumours were assayed for proliferative activity with anti-Ki-67 or anti-proliferating cell nuclear antigen (PCNA) antibodies. Cell apoptosis was examined using terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) assays and with caspase-3 immunostaining. Proteins were measured by Western blotting. Results There was a significant reduction in tumour volume and a reduced percentage of Ki-67-positive or PCNA-positive cells in the CP group compared with the control group. The percentage of TUNEL-positive or caspase 3-positive cells significantly increased following CP treatment compared with the control group. Tumours from the CP group had higher levels of phosphorylated-extracellular signal-regulated kinase (p-ERK) and phosphorylated-AKT (p-AKT) compared with control tumours. Conclusion CP treatment inhibited tumour growth and induced tumour cell apoptosis in a nude mouse model of BGC-823 gastric adenocarcinoma. Activation of the AKT and ERK signalling pathways may mediate this antitumour activity.

Three United Laparoscopic Surgery for the Treatment of Gastric Cardia Cancer-A Comparative Study with Laparotomy and Laparoscopy-Assisted Surgery.

BACKGROUND & AIM: Gastric cancer is a leading cause of cancer-related mortality worldwide. We have invented a novel hand-assist device that allows the placement of surgical instruments and the maneuvering of the surgeon's hand, and we have established a new hand-assisted laparoscopic technique called Three United Laparoscopic Surgery (TULS) for laparoscopic dissection of advanced gastric cancer. The present study aimed at exploring the usefulness of TULS in the treatment of advanced gastric cardia cancer. METHOD: A retrospective study on 100 patients with advanced gastric cardia cancer admitted from January 2014 to June 2015 was done. There were 38 cases of TULS, 30 cases of laparotomy, and 32 cases of laparoscopy-assisted surgery. Statistical comparisons between three treatment groups in operative time, incision length, amount of bleeding, number of lymph nodes dissected, time to flatus after surgery, rate of postoperative complications, hospital stay, and expense were done. RESULTS: For lymph node dissection, there were no significant differences between TULS, laparotomy, and laparoscopy-assisted surgery. However, compared with conventional laparotomy, TULS and laparoscopy-assisted surgery were found to be able to minimize incision length, reduce blood loss during surgery, lower postoperative complication rate, and shorten time to flatus and hospital stay. The differences were statistically significant (P < .05). The operative time of TULS was significantly shorter than that of the laparoscopy-assisted surgery (P < .05), and it was comparable to that of laparotomy. CONCLUSION: TULS is as efficient as laparotomy in lymph node dissection, and it shows the advantages of minimally invasive surgery. It can be considered a novel and promising surgical intervention for treatment of advanced gastric cancer.

S100A10 as a novel biomarker in colorectal cancer.

Recent data support the role of S100A10 in tumorigenesis. In this study, we evaluated the value of S100A10 positivity as a possible biomarker in colorectal cancer. We evaluated S100A10 positivity by immunohistochemistry in a large population of colorectal cancer patients (n = 882). The relationships between S100A10 positivity and clinicopathological features and clinical outcome were analyzed. There were 36 % (319/882) tumors positive for S100A10 in all colorectal cancer samples. In contrast, normal colorectal epithelium was negative for S100A10 among all 562 specimens of adjacent normal mucosa. S100A10 positivity was correlated with poor differentiation (p = 0.0012) and disease stage (p = 0.003). S100A10 positivity was significantly correlated with shortened specific [log-rank p < 0.001; multivariate hazard ratio (HR), 1.49; 95% confidence interval (CI), 1.09-2.04] and overall survival (log-rank p = 0.0012; multivariate HR, 1.34; 95% CI, 1.06-1.73). Knockdown of S100A10 by siRNA significantly reduced the proliferation, migration, and invasion capacity of colorectal cancer cell lines. Our results suggest a role for S100A10 as a prognostic marker and potential therapeutic target in colorectal cancer.

Association of epidermal growth factor +61 A/G polymorphism in Chinese patients with colon cancer.

Epidermal growth factor (EGF) plays an important role in tumorigenesis. The association between the +61 A/G polymorphism of the EGF gene and colon cancer risk remains controversial and unclear. The objective of this study was to investigate the association between EGF +61 A/G polymorphism and colon cancer risk in a Chinese population. A hospital-based case-control study was conducted to assess the possible association between EGF +61 A/G polymorphism and colon cancer risk. A total of 180 colon cancer patients and 180 cancer-free healthy controls were recruited in the Chinese population. Genomic DNA was isolated from peripheral blood, and gene polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Colon cancer patients had a significantly higher frequency of +61 GG genotype (odds ratio [OR]=1.93, 95% confidence interval [CI]=1.07, 3.50; p=0.03) than that of controls. When stratified by the tumor location, tumor size, growth pattern, differentiation, and tumor-node-metastasis (TNM) stage of colon cancer, no statistically significant results were observed. Our study revealed that EGF +61 GG genotype was associated with a higher risk of colon cancer in Chinese population.

Ultrasonically activated scalpel versus monopolar electrocautery shovel in laparoscopic total mesorectal excision for rectal cancer.

AIM: To investigate the feasibility and safety of monopolar electrocautery shovel (ES) in laparoscopic total mesorectal excision (TME) with anal sphincter preservation for rectal cancer in order to reduce the cost of the laparoscopic operation, and to compare ES with the ultrasonically activated scalpel (US). METHODS: Forty patients with rectal cancer, who underwent laparoscopic TME with anal sphincter preservation from June 2005 to June 2007, were randomly divided into ultrasonic scalpel group and monopolar ES group, prospectively. White blood cells (WBC) were measured before and after operation, operative time, blood loss, pelvic volume of drainage, time of anal exhaust, visual analogue scales (VAS) and surgery-related complications were recorded. RESULTS: All the operations were successful; no one was converted to open procedure. No significant differences were observed in terms of preoperative and postoperative d 1 and d 3 WBC counts (P=0.493, P=0.375, P=0.559), operation time (P=0.235), blood loss (P=0.296), anal exhaust time (P=0.431), pelvic drainage volume and VAS in postoperative d 1 (P=0.431, P=0.426) and d 3 (P=0.844, P=0.617) between ES group and US group. The occurrence of surgery-related complications such as anastomotic leakage and wound infection was the same in the two groups. CONCLUSION: ES is a safe and feasible tool as same as US used in laparoscopic TME with anal sphincter preservation for rectal cancer on the basis of the skillful laparoscopic technique and the complete understanding of laparoscopic pelvic anatomy. Application of ES can not only reduce the operation costs but also benefit the popularization of laparoscopic operation for rectal cancer patients.