Zhi-Dong Zhang

Zerumbone induces gastric cancer cells apoptosis: Involving cyclophilin A

Gastric cancer is one of the leading causes for cancer death. There is an urgent need to develop new therapeutic approaches targeting metastatic gastric cancer. It has been reported that zerumbone has the anti-cancer effects in various malignant cells. However, the effect and the mechanism of zerumbone on melanoma cells is still largely unknown. In the study, we determined the actions of zerumbone on the human gastric cancer cell line SGC-7901.We also observed the mechanism by which zerumbone induced gastric cancer cell apoptosis. Our data indicated that zerumbone significantly inhibited the growth of human gastric cancer cells in a dose-dependent manner and apoptosis was the main cause of decreased cell viability in zerumbone -treated cells. The treatment with zerumbone downregulated Cyp A and Bcl-2 levels, upregulated Bax levels, and caused Cytochrome c (Cyt-C) to release, activating Caspase-3. In summary, our study suggests that zerumbone mightinduced human gastric cancer cells apoptosis through down-regulating Cyp A and mitochondria-mediated pathways.

Effect of annexin A7 suppression on the apoptosis of gastric cancer cells

Understanding the molecular mechanism of gastric cancer cell apoptosis is pivotal for the development of precise therapies targeting this disease. In the present study, we examined the effects of annexin A7 inhibition on the apoptosis of gastric cancer cells and the growth of tumour xenografts in vivo. Expression of annexin A7 in BGC823 cells was suppressed by small interference RNA, and cells apoptosis was assessed by flow cytometry. The mechanism by which annexin A7 mediates apoptosis in BGC823 cells was explored by determining the expression of key apoptosis regulators. In addition, by suppressing annexin A7 in BGC823 cells with small hairpin RNA, we studied the effects of annexin A7 inhibition on in vivo tumour growth. Our results showed that inhibiting annexin A7 expression induced more than fivefold increase in BGC823 cell apoptosis in vitro. This was in concord with a significant decrease of Bcl-2 expression and increases of Bax, Caspase-3, and Caspase-9. The activities of caspase-3 and caspase-9 were increased by 2.95 ± 0.18 and 3.70 ± 0.33 times, respectively, upon the annexin A7 downregulation in BGC823 cells. Importantly, suppressing annexin A7 showed the same apoptotic mechanism in vivo and significantly inhibited the growth of BGC823 xenografts in mice. These data suggest that annexin A7 likely protects gastric cells from apoptosis and targeting it may represent a valuable strategy in future therapeutic development.

Gastrointestinal stromal tumor (gist) with liver metastases: An 18-year experience from the Gist cooperation group in North China

Abstract Approximately 40% to 50% of gastrointestinal stromal tumor (GIST) patients will have recurrence or metastases after resection of the primary lesion, and the most common affected sites will be liver and peritoneum. Imatinib has been considered as the first-line therapy of metastatic GIST. Surgery for metastases is proposed when possible. Furthermore, there are controversies concerning hepatic resection and systemic tyrosin kinase inhibitors (TKIs). The therapeutic conditions and long-term outcome of GIST patients with liver metastases in northern China remain unknown. The clinical, pathological, and follow-up data of 144 GIST patients, who had liver metastases between June 1996 and June 2014 from 3 tertiary cancer centers in northern China, were reviewed. Thirty-two cases (22.2%) had hepatectomy with 23 (23/32, 71.9%) R0 resections and 9 (9/32, 28.1%) R1/R2 resections, respectively. Twenty-three patients were given imatinib postoperatively. Furthermore, 98 (68.1%) patients were given TKIs only to control disease progression, and sunitinib was considered after imatinib failure in 12 patients. The 1-, 3- and 5-year survival rate was 82%, 51%, and 24%, with a median overall survival of 48 months for all patients. Patients who had hepatic resection combined with TKIs had a tendency of improved outcome, and the median survival time was 89 months. This was in contrast to patients who received TKIs only, in which median survival time was 53 months. Patients who received imatinib plus sunitinib had a tendency of longer survival time, compared with patients who received imatinib only (not reached vs 50 months). TKIs combined with hepatic resection had a role in improving the outcome of GIST patients with liver metastases.

Annexin A7 expression is downregulated in late‑stage gastric cancer and is negatively correlated with the differentiation grade and apoptosis rate

Annexin A7 is a member of the Annexin A family, which participates in various biological processes. Accumulating evidence has demonstrated that Annexin A7 serves an important role in tumorigenesis and is dysregulated in multiple types of cancer. However, the role of Annexin A7 in the tumorigenesis of gastric cancer remains to be determined. The present study revealed that Annexin A7 expression is downregulated in late-stage gastric cancer and is negatively correlated with the differentiation grade and apoptosis. There was a significant difference in Annexin A7 mRNA and protein expression in gastric cancer samples with distinct differentiation grades, with the lowest expression being observed in the highly differentiated cases. A terminal deoxynucleotidyl-transferase-mediated dUTP nick end labelling assay demonstrated that the apoptosis indices of highly, moderately and poorly differentiated gastric cancers were 18.12±2.40, 9.73±1.73 and 4.13±0.83%, respectively, with statistical significance (P<0.05). Flow cytometric analysis demonstrated that the apoptosis rates of gastric cancer MKN74, SGC7901 and BGC823 cells were 10.07±1.21, 7.11±1.04 and 4.25±1.02%, respectively, with statistical significance (P<0.05). Spearmans rank correlation analysis revealed that the Annexin A7 mRNA and protein levels were negatively correlated with the differentiation grade of the gastric cancer tissues, while the apoptosis index was positively correlated with the differentiation grade of the gastric cancer tissues. Furthermore, the apoptosis index was negatively correlated with Annexin A7 mRNA and protein expression. Similar associations were observed among Annexin A7 expression, differentiation grades and apoptosis in gastric cancer cell lines. The results of the present study demonstrated that Annexin A7 expression is downregulated, while apoptosis is upregulated, with the progression of gastric adenocarcinoma. These observations suggested that Annexin A7 may inhibit apoptosis during tumorigenesis and that it is a potential biomarker for the diagnosis, prognosis and treatment of gastric adenocarcinoma.

Overexpression of stromal interaction molecule 1 may promote epithelial‑mesenchymal transition and indicate poor prognosis in gastric cancer

The aim of the present study was to investigate the prognostic significance of stromal interaction molecule 1 (STIM1) expression in gastric cancer (GC) and examine the association between STIM1 and epithelial-mesenchymal transition (EMT). Immunohistochemical staining was performed to detect STIM1, E-cadherin, β-catenin and matrix metalloproteinase-9 (MMP-9) in 170 GC and 35 adjacent healthy gastric tissue samples. Positive staining of STIM1, E-cadherin, β-catenin and MMP-9 in GC tissues was significantly greater compared with adjacent healthy tissues (P<0.05). Clinicopathological analysis revealed that STIM1 expression was significantly associated with LNM (P<0.001) and tumor-node-metastasis stage (P=0.01). The overall survival rate was significantly reduced in STIM1-positive compared with STIM1-negative patients (P=0.043). Cox regression analysis indicated that STIM1 expression and LNM were independent prognostic factors for GC. Chi-square tests suggested that STIM1 expression in GC tissues was significantly associated with E-cadherin (P<0.001) and β-catenin (P<0.001), whereas no association was observed between STIM1 and MMP-9 expression (P>0.05). In conclusion, the results of the present study suggested that STIM1 may be a valuable prognostic marker in GC patients, and that STIM1 may increase GC motility and invasiveness by promoting epithelial-mesenchymal transition.

630PCONCURRENT NEOADJUVANT CHEMORADIOTHERAPY FOR SIEWERT II AND III ADENOCARCINOMA OF THE GASTROESOPHAGEAL JUNCTION: SHORT TERM EFFICACY

ABSTRACT Aim: This study was conducted to investigate the efficacy and safety of applying concurrent neoadjuvant chemoradiotherapy in treatment of adenocarcinoma of the gastroesophageal junction. Methods: From August 2012 to August 2013, a total of 76 patients with resectable adenocarcinoma of the gastroesophageal junction (T3/4,N + ,M0) were recruited and randomly assigned to a concurrent chemoradiotherapy group (n = 36) or a surgery group (n = 40). Patients in the chemoradiation group received oral administration of capecitabine (1000 mg/m2, bid, for 14 days), and intravenous administration of oxaliplatin (130 mg/m2 on day 1, q3w, for 2 courses). A total of 45 Gy radiations were administered during a period of 5 weeks (25 sessions). Patients in the surgery group received surgical intervention alone. This study was approved by the ethics committee and registered in ClinicalTrials.gov(NCT01962246). Results: In the concurrent chemoradiotherapy group, the overall response rate was 55.6% (20/36), the tumor control rate was 100%, and pathological complete response was achieved in 6 of 36 patients (16.7%). The proportion of patients who achieved R0 resection in the concurrent chemoradiotherapy group and surgery group was 100% and 80% (32/40), respectively (P Complications Concurrent chemoradiotherapy (n = 36) Surgery alone (n = 40) Lymphatic fistula 1 (27.8) 0 Pleural effusion and ascites 1 (27.8) 0 Esophageal-jejunal anastomotic fistula 0 1 (25) Wound dehiscence 0 1 (25) Conclusions: Administration of concurrent neoadjuvant chemoradiotherapy increased the rate of R0 resection and well tolerated in patients with Siewert II or III adenocarcinoma of the gastroesophageal junction. A phase III trial is planned to further proof this concept. Disclosure: All authors have declared no conflicts of interest.