HOXC10 indicates poor survival outcome in gastric cancer and promotes G1/S cell cycle transition through transcriptional repression of p21.

Homeobox (HOX) genes encode proteins that function as transcription factors during embryogenesis and tumorigenesis. We have previously reported upregulation of HOXC10 in gastric cancer (GC) tissues using cDNA microarray analysis. Though the functional role of HOXC10 in GC has been briefly reported, its specific mechanism is not fully understood. We analyzed the expression of HOXC10 in GC tissues, as well as its correlation with the survival outcome. By in vitro and in vivo assays, we further investigated the role of HOXC10 on cell cycle control and proliferation. Finally, we screened potential downstream targets of HOXC10 by cDNA microarray and explored the role of HOXC10 in p21 transcriptional repression through a dual luciferase reporter and chromatin immunoprecipitation. We illustrated the upregulation of HOXC10 in GC tissues and high HOXC10 expression related to poor survival outcome. Multivariable COX regression analysis showed that HOXC10 was an independent predictor of survival (HR=1.863; 95% CI: 1.076-3.225). Functionally, HOXC10 could promote GC cell proliferation and tumor growth in nude mice. Overexpression of HOXC10 accelerated G1/S cell cycle transition, whereas knocking down HOXC10 induced cell cycle arrest at the G1 phase. Critical factors of G1/S cell cycle transition including p21, CDK2, and c-Myc, were regulated by HOXC10. Importantly, an inverse correlation between p21 and HOXC10 expression in GC cell lines and tissues was observed. HOXC10 could directly bind to the promoter region of p21 and repress its transcriptional activity. Collectively, we identified HOXC10 as a predictor of poor prognosis in GC patients, and a novel transcriptional regulator of p21 in the G1/S cell cycle transition.

Role of plasmacytoid dendritic cells and inducible costimulator-positive regulatory T cells in the immunosuppression microenvironment of gastric cancer.

Regulatory T cells (Tregs) and plasmacytoid dendritic cells (pDCs) play important roles in the immune escape of cancer. In this study, we investigated pDCs and pDC-induced inducible costimulator (ICOS)(+) Treg populations in peripheral blood from gastric cancer (GC) patients and healthy donors by flow cytometry. The distribution of these cells in carcinoma tissue, peritumor tissue, and normal gastric mucosa was detected by immunohistochemistry. Plasma and tissue concentration of the cytokines such as interleukin-10 and transforming growth factor-ß1 were also measured. We found that the numbers of pDCs, Tregs, and ICOS(+) Tregs in peripheral blood were increased in GC patients compared with healthy donors. In tissue, Tregs and ICOS(+) Tregs were found distributing mainly in carcinoma tissue, whereas pDCs were mainly found in peritumor tissue. Moreover, the Foxp3(+) ICOS(+) /Foxp3(+) cell ratio in carcinoma and peritumor tissue were higher than that in normal tissue. There were more ICOS(+) Tregs in tumor and peritumor tissue of late-stage GC patients. There was a positive correlation between pDCs and ICOS(+) Tregs in peripheral blood and peritumor tissue from GC patients. In conclusion, pDCs may play a potential role in recruiting ICOS(+) Tregs, and both participate in the immunosuppression microenvironment of GC.

Anti-tumor effects of Mfn2 in gastric cancer.

Mitofusin-2 (Mfn2) is a mitochondrial outer membrane protein involved in mitochondrial fusion. Its mutation can cause Charcot-Marie-Tooth disease. Recent studies of Mfn2 in cancer research have not included gastric cancer. We confirmed that Mfn2 expression was lower in tumor tissue than in normal gastric mucosal tissue and that it was negatively correlated with tumor size, indicating an anti-tumor role for Mfn2. In vitro experiments showed that Mfn2 overexpression suppressed gastric cancer cell proliferation and colony formation, weakened the invasion and migratory ability of cancer cells by downregulating MMP-2 and MMP-9, halted the cell cycle and induced apoptosis. Western blotting indicated the likely involvement of P21 and PI3K/Akt signaling. Therefore, Mfn2 is a potential anti-tumor gene and a potential therapeutic target for treating gastric cancer. The progress of gastric cancer may be delayed by controlling Mfn2 expression.

Regulatory T Cells Promote Overexpression of Lgr5 on Gastric Cancer Cells via TGF-beta1 and Confer Poor Prognosis in Gastric Cancer.

Background: The leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5) is considered a cancer stem cell marker, and is often overexpressed in tumors. The interaction between Lgr5 and the immune-related tumor microenvironment is not completely understood. The aim of this study was to examine the role of Lgr5 in the microenvironment of gastric cancer (GC), and to explore possible immunological mechanisms influencing Lgr5 expression that are governed by regulatory T cells. Methods: Lgr5 expression was examined in 180 GC tumors by immunohistochemistry, and in 80 pairs of GC tumors for analysis of Th1/Th2 cytokines by ELISA. In addition, SGC7901 cells were co-cultured with patient-derived Tregs, varying concentrations of TGF-ß1, TGF-ß1 neutralizing antibody, or TGF-ß receptor inhibitor SB431542, and Lgr5 and ß-catenin expression were examined by qRT-PCR and western blot. Results: In this study, an immunosuppressive microenvironment was associated with high Lgr5 expression in GC. Furthermore, Lgr5 expression was up-regulated in GC cells co-cultured with Tregs or treated with exogenous TGF-ß1. This up-regulation was partially inhibited by the TGF-ß1 neutralizing antibody, or TGF-ß1 receptor antagonist SB431542. ß-catenin was up-regulated with high Lgr5 expression induced by exogenous TGF-ß1, and this up-regulation was inhibited by SB431542. An increased number of Tregs and high Lgr5 expression in GC tissues were significantly associated with low overall survival. Conclusion: Tregs promoted increased Lgr5 expression in GC cells via TGF-ß1 and TGF-ß1 signaling pathway, which may involve activation of the Wnt signaling pathway. High Lgr5 expression via TGF-ß confer poor prognosis in gastric cancer.

Neoadjuvant chemotherapy in controlling lymph node metastasis for locally advanced gastric cancer in a Chinese population.

This study aimed to evaluate the efficacy of FOLFOX6, SOX and XELOX as neoadjuvant chemotherapy for advanced gastric cancer. The study retrospectively assessed clinicopathological data of patients who received a radical D2 gastrectomy for gastric cancer from January 2010 to January 2013.The patients were either not administered neoadjuvant chemotherapy (control) or were given FOLFOX6, SOX and XELOX prior to surgery. The metastatic rate was also higher for the control group compared with the three chemotherapy regimens in N2 station lymph nodes (P < 0.001). The SOX group had significantly lower metastatic total and N2 station lymph nodes than FOLFOX6 and XELOX (P < 0.01). The frequency of metastatic lymph nodes relative to total lymph nodes examined was 9.9, 6.6, 3.9 and 5.3% for control, FOLFOX6, SOX and XELOX groups, respectively. In conclusion, SOX may be the most effective of these treatments as preoperative chemotherapy for Chinese patients with advanced gastric cancer.

Attenuation of graft ischemia-reperfusion injury by urinary trypsin inhibitor in mouse intestinal transplantation.

AIM: Ischemia/reperfusion (I/R) injury is one of the major obstacles for intestinal transplantation (ITx). Urinary trypsin inhibitor (Ulinastatin, UTI) suppresses proteases and stabilizes lysosomal membranes. We supposed that Ulinastatin would diminish I/R injury of intestinal graft. METHODS: UTI- treated group and untreated control group were investigated by histological assessment at 1.5, 4, 24, and 72 h after ITx. Myeloperoxidase (MPO) activity was used as the activity of neutrophils, and malondialdehyde (MDA) was used as an index of lipid peroxidation. TNFalpha and i-NOS mRNA expression in graft tissue were measured by semi-quantitative RT-PCR. CD11b+Gr1+ cells in graft lamina propria were analyzed by flow cytometry. RESULTS: Histological scores of the graft showed that the tissue injury was markedly attenuated by UTI treatment at different time points after ITx, with reduced MPO and MDA value in the grafts. The expression of TNFalpha and i-NOS mRNA was profoundly inhibited, while the infiltration of CD11b+ Gr1+ cells into the intestinal graft was decreased in UTI group. CONCLUSION: Urinary trypsin inhibitor attenuates I/R injury in mouse intestinal transplantation by reducing monocytes infiltration and down-regulation of TNFalpha and i-NOS mRNA expression.

Expression of cyclooxygenase-2 in gastric cancer and its relation to liver metastasis and long-term prognosis.

AIM: To investigate the expression of cyclooxygenase-2 (COX-2) in gastric cancer and its relation with the liver metastasis and prognosis. METHODS: Expression of COX-2 mRNA and protein was examined in gastric cancer and its paired substantial normal tissue by semi-quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. The relation between COX-2 expression and prognosis was investigated in 195 cases. RESULTS: The expression of COX-2 mRNA in gastric cancer tissue was significantly higher than that in normal tissue in 47 cases (w = 792, P<0.01). The COX-2 mRNA in pT3-4 tissue expressed higher than that in pT1-2 tissue (w = 204, P<0.05). The positive expression rate of COX-2 protein was 57.9% (113/195). The COX-2 expression was significantly related to histological type, lymphnode metastasis, venous invasion and liver metastasis (P<0.05). No relation was found between COX-2 expression and invasion depth, peritoneal metastasis and International Union against Cancer TNM stage. The multiple regression analysis showed that the COX-2 expression and venous invasion were obviously associated with liver metastasis (P<0.05). However, there was no significant correlation between COX-2 immunoreactivity and prognosis. CONCLUSION: COX-2 may play an important role in the development of gastric cancer, and the over-expression of COX-2 protein may be a high risk factor for liver metastasis.

Symptomatic adult annular pancreas: report of two cases and a review of the literature.

BACKGROUND: Annular pancreas in adults is a rare embryologic abnormality detected after development of complications. Embryology, diagnosis and treatment strategies for symptomatic adult annular pancreas remain controversial. In this paper we reevaluated these problems in view of the technological and theoretical advances. METHODS: In 2 patients with annular pancreas, one(36-year-old male patient) presenting with duodenal obstruction and duodenal ulcer associated with duodenocolic fistula underwent Billroth II gastrectomy and fistula ectomy and the other(17-year-old male patient) presenting with duodenal obstruction and duodenal ulcer underwent Billroth II gastrectomy. English language literature about annular pancreas etiology, diagnosis and treatment was reviewed. RESULTS: Both of the patients had uneventfully recovered. Abdominal computed tomography, endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography showed typical images of annular pancreas. Duodenal bypass procedure, choledochojejunostomy, endoscopic sphincterotomy or biliary stenting, and pancreatic resection were alternative to treat this sort of anomaly. CONCLUSIONS: Annular pancreas in adults is a rare congenital abnormality, while newer imaging modalities and an index of suspicion may assist in finding more cases. The management of this congenital anomaly should be individualized according to the associated complications.

Primary gastrointestinal stromal tumor of the liver treated with sequential therapy.

A 67-year-old female presented with a primary hepatic gastrointestinal stromal tumor that was detected by computed tomography and diagnosed based on histopathological and genetic analyses. The tumor was microscopically composed of spindle cells and epithelioid cells, and immunohistochemistry results showed positive staining for CD117 and CD34 expression. A genetic analysis revealed a heterozygous point mutation and deletion in exon 11 of c-KIT. After an R0 resection, imatinib mesylate was administered for 1 year until its use was discontinued due to severe side effects. Two years after the original operation, the tumor recurred in the residual liver and was completely resected again. Imatinib mesylate was administered for 2 years until it was replaced by sunitinib malate because of disease progression. The patient has survived for 53 mo after undergoing a sequential therapy consisting of surgical excision, imatinib and sunitinib.

Meta-analysis of robotic and laparoscopic surgery for treatment of rectal cancer.

AIM: To conduct a meta-analysis to determine the relative merits of robotic surgery (RS) and laparoscopic surgery (LS) for rectal cancer. METHODS: A literature search was performed to identify comparative studies reporting perioperative outcomes for RS and LS for rectal cancer. Pooled odds ratios and weighted mean differences (WMDs) with 95% confidence intervals (95% CIs) were calculated using either the fixed effects model or random effects model. RESULTS: Eight studies matched the selection criteria and reported on 661 subjects, of whom 268 underwent RS and 393 underwent LS for rectal cancer. Compared the perioperative outcomes of RS with LS, reports of RS indicated favorable outcomes considering conversion (WMD: 0.25; 95% CI: 0.11-0.58; P = 0.001). Meanwhile, operative time (WMD: 27.92, 95% CI: -13.43 to 69.27; P = 0.19); blood loss (WMD: -32.35, 95% CI: -86.19 to 21.50; P = 0.24); days to passing flatus (WMD: -0.18, 95% CI: -0.96 to 0.60; P = 0.65); length of stay (WMD: -0.04; 95% CI: -2.28 to 2.20; P = 0.97); complications (WMD: 1.05; 95% CI: 0.71-1.55; P = 0.82) and pathological details, including lymph nodes harvested (WMD: 0.41, 95% CI: -0.67 to 1.50; P = 0.46), distal resection margin (WMD: -0.35, 95% CI: -1.27 to 0.58; P = 0.46), and positive circumferential resection margin (WMD: 0.54, 95% CI: 0.12-2.39; P = 0.42) were similar between RS and LS. CONCLUSION: RS for rectal cancer is superior to LS in terms of conversion. RS may be an alternative treatment for rectal cancer. Further studies are required.

Acute cholecystitis immediately after radical gastrectomy: a report of three cases.

Acute cholecystitis is not a common complication of gastrectomy. Its clinical presentations and management strategies in old patients have not been well described in available literature. This report describes the clinical features, management strategies, and treatment outcome of acute cholecystitis immediately after gastrectomy. Acute cholecystitis immediately after gastrectomy in old patients has different clinical presentations, such as fever and high plasma C-reaction protein level. Abdominal computed tomography (CT) scan and ultrasonography showed acute cholecystitis in our cases, which was treated with antibiotics and ultrasound-guided percutaneous transhepatic gallbladder drainage (PTGD). The results indicate that abdominal CT scan and ultrasonography can effectively diagnose acute cholecystitis after gastrectomy, which can be effectively treated with antibiotics and PTGD.

Gastrointestinal stromal tumor of stomach with inguinal lymph nodes metastasis: a case report.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the alimentary tract. To the best of our knowledge, few cases have been reported in the literature about the peripheral lymph node metastasis of GIST. Here we report an unusual case of gastric GIST with inguinal lymph nodes metastasis. After the metastatic lymph nodes were resected, the. patient started to take imatinib 400 mg/d for 12 mo. There were no signs of tumor recurrence at follow-up after 29 mo. This case suggests that the inguinal lymph nodes can be a potential metastatic site of GIST.