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Pancreatic cancer is always diagnosed at an advanced stage. Hence, chemotherapy becomes the best choice for patients. Therefore, new anticancer drugs for pancreatic cancer are needed. Riluzole (RIL) is mainly used to treat amyotrophic lateral sclerosis clinically, but many previous studies have shown that RIL could inhibit tumors. However, no report has explored the association between RIL and pancreatic cancer. To validate this association, we performed this study. Our data showed that RIL could induce cytotoxicity, block the cell cycle, and inhibit clone formation, apoptosis, and migration in pancreatic cancer cells. Moreover, we demonstrated that RIL could suppress autophagy. However, more experiments will be needed to validate the reliability of our conclusions. In summary, our data suggest that RIL might provide clues for the development of a treatment for human pancreatic cancer in the future.

In this study, we investigated the role of Fat atypical cadherin 4 (FAT4) in gastric cancer (GC) progression. Immunohistochemical analysis showed lower FAT4 expression in tumor tissues from GC patients than in normal gastric epithelium. Lower FAT4 expression was associated with poor prognosis, tumor size and invasion, and lymph node and distant metastases. Multivariate analysis showed that TNM stage, lymph node and distant metastases, Lauren classification, and FAT4 expression were independent prognostic factors in GC. Methylation-specific PCR analysis showed increased FAT4 promoter methylation in GC tumor tissues and cell lines. Higher FAT4 promoter methylation was associated with low FAT4 expression and a poor prognosis. BGC-823 cells showed increased FAT4 expression upon treatment with 5-azacytidine, demethylating agent. FAT4 knockdown in BGC-823 cells led to increased cell proliferation, migration and invasiveness. Moreover, xenografts of BGC-823 cells with FAT4 knockdown showed enhanced tumor growth and metastasis in nude mice. These findings demonstrate that low FAT4 expression is associated with a poor prognosis in GC patients.

Prolyl hydroxylase 3 (PHD3) is widely accepted as a tumor suppressor; however, the expression of PHD3 in various cancer types remains controversial. The present study aimed to investigate the association between PHD3 expression and the clinicopathological features of gastric cancer using reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry. The effects of PHD3 in gastric cancer cell lines were assessed using western blot analysis and transwell migration assays. The present results revealed that PHD3 expression was increased in adjacent non‑cancerous tissue compared with in gastric cancer tissue, and PHD3 overexpression was correlated with the presence of well‑differentiated cancer cells, early cancer stage classification and the absence of lymph node metastasis. In vitro experiments demonstrated that PHD3 may act as a negative regulator of hypoxia‑inducible factor‑1α and vascular endothelial growth factor, both of which participate in tumor angiogenesis. In conclusion, the present results suggested that PHD3 may act as a tumor suppressor in gastric cancer. Therefore, the targeted regulation of PHD3 may have potential as a novel therapeutic approach for the treatment of patients with gastric cancer.

Increased expression of HOXB7 has been reported to correlate with the progression in many cancers. However, the specific mechanism by which it promotes the evolution of gastric cancer (GC) is poorly understood.In this study, we sought to investigate the role of HOXB7 in GC by assessing HOXB7 expression in patient tissue and its correlation to clinical characteristics. We found that GC tissues showed increased expression of HOXB7 and that the HOXB7 expression was significantly associated with Lauren classification, invasion depth, lymphatic metastasis and poor prognosis, and could serve as an independent prognostic factor. To further investigate the role of HOXB7 in GC, we generated stable GC cell lines and both over-expressed and knocked down HOXB7 expression. Over-expression of HOXB7 in GC cell lines enhanced cell proliferation, colony formation, migration and invasion ability, whereas the opposite trends were observed upon reduction of HOXB7 expression by knockdown. These findings were further supported by our in vivo studies which show that HOXB7 expression can affect the GC cells' subcutaneous growth and lung metastases. A Phospho-MAPK Array Kit was used to explore the possible mechanism of HOXB7-induced cell proliferation and invasion. We found that the AKT signaling pathway and the two members of the MAPK pathway, were involved in those promoting effects. In conclusion, our results showed that increased expression of HOXB7 might play an important role in promoting GC proliferation, migration and invasion by inducing both AKT and MAPK pathways, thus resulting in progression of, and poor prognosis in GC patients.

Background Several somatic mutation hotspots were recently identified in the telomerase reverse transcriptase (TERT) promoter region in human cancers. Large scale studies of these mutations in multiple tumour types are limited, in particular in Asian populations. This study aimed to: analyse TERT promoter mutations in multiple tumour types in a large Chinese patient cohort, investigate novel tumour types and assess the functional significance of the mutations. Methods TERT promoter mutation status was assessed by Sanger sequencing for 13 different tumour types and 799 tumour tissues from Chinese cancer patients. Thymic epithelial tumours, gastrointestinal leiomyoma, and gastric schwannoma were included, for which the TERT promoter has not been previously sequenced. Functional studies included TERT expression by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), telomerase activity by the telomeric repeat amplification protocol (TRAP) assay and promoter activity by the luciferase reporter assay. Results TERT promoter mutations were highly frequent in glioblastoma (83.9%), urothelial carcinoma (64.5%), oligodendroglioma (70.0%), medulloblastoma (33.3%) and hepatocellular carcinoma (31.4%). C228T and C250T were the most common mutations. In urothelial carcinoma, several novel rare mutations were identified. TERT promoter mutations were absent in gastrointestinal stromal tumour (GIST), thymic epithelial tumours, gastrointestinal leiomyoma, gastric schwannoma, cholangiocarcinoma, gastric and pancreatic cancer. TERT promoter mutations highly correlated with upregulated TERT mRNA expression and telomerase activity in adult gliomas. These mutations differentially enhanced the transcriptional activity of the TERT core promoter. Conclusions TERT promoter mutations are frequent in multiple tumour types and have similar distributions in Chinese cancer patients. The functional significance of these mutations reflect the importance to telomere maintenance and hence tumourigenesis, making them potential therapeutic targets.

Background: This study aimed to summarize the potential diagnostic value of serum DKK1 levels in cancer detection. Materials and Methods: Serum DKK1 was measured using enzyme-linked immunosorbent assay in a case-control study. Then we performed a meta-analysis and the pooled sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic (sROC) curves were used to evaluate the overall test performance. Results: Serum DKK1 levels were found to be significantly upregulated in gastric cancer as compared to controls. ROC curve analysis revealed an AUC of 0.636, indicating the test has the potential to diagnose cancer with poor accuracy. The summary estimates of the pooled sensitivity, specificity and diagnostic odds ratio in meta-analysis were 0.55 with a 95% confidence interval (CI) (0.53-0.57), 0.86 (95% CI, 0.84-0.88) and 12.25 (95% CI, 5.31-28.28), respectively. The area under the sROC was 0.85. Subgroup analysis revealed that the diagnostic accuracy of serum DKK1 in lung cancer (sensitivity: 0.69 with 95% CI, 0.66-0.74; specificity: 0.95 with 95% CI, 0.92-0.97; diagnostic odds ratio: 44.93 with 95% CI, 26.19-77.08) was significantly higher than for any other cancer. Conclusions: Serum DKK1 might be useful as a noninvasive method for confirmation of cancer diagnosis, particularly in the case of lung cancer.

Background Recently, there have been a number of studies on the association between MDM2 (Murine Double Minute 2) 309 polymorphism and ovarian cancer risk. However, the results of previous reports remain controversial and ambiguous. Thus, we performed a meta-analysis to explore more precisely the association between MDM2 309 polymorphism and the risk of ovarian cancer. Methods A meta-analysis was performed to examine the association between MDM2 309T>G polymorphism and ovarian cancer risk. Odds ratio (OR) and its 95% confidence interval (CI) were used for statistical analysis. Results Our publication search identified a total of 6 studies with 1534 cases and 2211 controls. No significant association was found between MDM2 309T>G polymorphism and ovarian cancer risk in total population analysis. In the subgroup meta-analysis by ethnicity, a negative association was shown in Asian subgroup (G vs. T OR = 0.774, 95% CI = 0.628–0.955, P = 0.017, P het = 0.327; GG vs. TT: OR = 0.601, 95% CI = 0.395–0.914, P = 0.017, P het = 0.417; dominant model TG+GG vs. TT: OR = 0.661, 95% CI = 0.468–0.934, P = 0.019, P het = 0.880), and no significant association in any genetic models among Caucasians was observed. Conclusions This meta-analysis provides evidence for the association between MDM2 309 polymorphism and ovarian cancer risk, supporting the hypothesis that MDM2 SNP309 G allele acts as an important ovarian cancer protective factor in Asians but not in Caucasians.

Recent studies have shown that overexpression of regenerating gene family member 4 ( REG 4 ) is associated with the initiation and progression of pancreatic cancer. In our study, we explored the role of REG 4 in the invasion of pancreatic cancer. Real‐time PCR and Western blot analysis were used to determine REG 4 expression in pancreatic cancer cell lines. An MTT assay was carried out to test the effect of REG 4 on the growth of pancreatic cancer cells. The involvement of REG 4 in cancer cell invasion was examined by Transwell invasion assay. Two MMP s, MMP ‐7 and MMP ‐9 , were identified from a pool of candidate genes as being related to REG 4 ‐induced cell invasion by PCR and Western blotting. Immunohistochemistry was used to confirm the correlation between REG 4 and the two MMP s. High expression of REG 4 was found in BXPC ‐3 cells and its culture media. But in PANC ‐1 and ASPC ‐1 cell lines, REG 4 expression levels were very low, and no detectable protein was found in the culture medium. The MTT and Transwell invasion assays showed that recombinant REG 4 protein and BXPC ‐3 conditioned media significantly promoted the proliferation and invasiveness of pancreatic cancer cells. It was also shown that MMP ‐7 and MMP ‐9 are upregulated by REG 4 induction using real‐time PCR and Western blotting analysis. Immunohistochemical study further verified this result. In conclusion, REG 4 promotes not only growth but also in vitro invasiveness of pancreatic cancer cells by upregulating MMP ‐7 and MMP ‐9.

The aim of this study was to explore the clinical significance of neutrophil gelatinase‐associated lipocalin (NGAL) in the development and prognosis of gastric cancer. NGAL tumor levels were determined in 333 GC patients by immunohistochemistry. NGAL in blood samples from 63 healthy donors and 60 gastric cancer patients were also determined by enzyme‐linked immunosorbent assay. Rate of NGAL expression was correlated with the size of tumor (69.3% in >4 cm tumors vs. 46.1% in ≤4 cm tumors), Lauren's classification (84.3% in diffuse type vs. 28.2% in intestinal type), lymph node metastasis (75.6% vs. 16.4% with no metastasis), vascular invasion (74.9% vs. 26.8% with no invasion), distant metastasis (94.3% vs. 50.3% with no distant metastasis), and TNM stage (81.8% in TNM III+IV vs. 20.5% in TNM I+II). NGAL expression can be used as an independent prognostic factor in gastric cancer as indicated by multivariate analysis. Positivity for serum NGAL was higher than that for carbohydrate antigen determinant, CA19‐9 (38.1% vs. 12.5%) in TNM I, and higher than that for carcinoembryonic antigen, CEA (58.3% vs. 8.3%) and CA19‐9 (58.3% vs. 8.3%) in TNM II. In conclusion, serum NGAL has great potential to be used as an ancillary test for diagnosis of gastric cancer. Increased expression of NGAL in tumors suggests gastric cancer is likely to be at an advanced stage with invasion and metastasis, and also poor prognosis. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.

MicroRNAs (miRNAs) are short non-coding RNA molecules playing regulatory roles by repressing translation or cleaving RNA transcripts. Dysregulated expression of miRNAs is associated with several diseases, including cancer. In this study, we report that the expression of microRNA-101 (miR-101) is down-regulated in gastric cancer tissues and cells, and ectopic expression of miR-101 significantly inhibits cellular proliferation, migration and invasion of gastric cancer cells by targeting EZH2, Cox-2, Mcl-1 and Fos. Our animal study also indicates that miR-101 could potentially suppress tumour growth in vivo. Collectively, these results suggest that miR-101 may function as a tumour suppressor in gastric cancer, as it has an inhibitory role not only in cellular proliferation, migration and invasion in vitro, but also in tumour growth in vivo.

OBJECTIVE:To study the effect of angiogenesis inhibitor SU6668 on the growth and metastasis of gastric cancer in SCID mice.METHODS:Metastatic model was established by orthotopic implantation of histologically intact human tumor tissue into the gastric wall of SCID mice. Forty-eight mice were randomly divided into four groups, and saline, 5-FU, SU6668, and 5-FU plus SU6668 were administered by i.p. every day for 6 weeks after tumor implantation. The mice were killed and tumor weight, tumor inhibition rate, intratumoral microvessel density(MVD), apoptotic index(AI) and metastasis inhibition were evaluated.RESULTS:Compared with the control, tumor growth was significantly inhibited in mice treated respectively with 5-FU, SU6668 and 5-FU plus SU6668 with inhibition rates of 47.5%, 64.1% and 69.2% respectively. Decreased MVD and increased AI were noted in the mice treated with SU6668 and 5-FU plus SU6668. The incidences of liver and peritoneal metastases was significantly inhibited and decreased to 62.5%, 69.9% in SU6668 group, and 74.9%, 90% in 5-FU plus SU6668 group. The growth and metastasis of human gastric cancer implanted in SCID mice were significantly inhibited in SU6668 group and combined group, especially in combined group.CONCLUSION:Angiogenesis inhibitor SU6668 has a strong inhibitory effect on tumor growth and metastasis of human gastric cancer transplanted in SCID mice, and has synergistic effect combined with cytotoxic agents.

BACKGROUND:Although a variety of tumor markers are available for diagnosis of pancreatic cancer, their sensitivity and specificity have not yet been ideal. The aims of this study was to detect a panel of serum tumor markers and to evaluate their significance in the diagnosis and prognosis of pancreatic cancer patients.METHODS:Eight serum tumor markers including AFP, CEA, CA-50, CA72-4, CA-125, CA153, CA19-9 and CA242 were detected in 129 patients with pancreatic cancer by using chemiluminescence immunoassay, immunofluorescence assay and immunoradiometric assay, respectively. The levels of these markers were compared in 99 patients with non-pancreatic malignant tumor, 63 patients with other benign diseases, and 27 patients with pancreatic cancer after pancreatectomy.RESULTS:Among the 8 tumor markers, CA19-9, CA242, CA-50, and CA72-4 were more sensitive in the diagnosis of pancreatic cancer. Parallel combined testing could increase the diagnostic sensitivity to 89.2%, and serial combined examination could increase the diagnostic specificity to 92.3%. The serum tumor markers levels were decreased significantly after radical tumor resection.CONCLUSIONS:Serum CA19-9, CA242, CA-50, and CA72-4 are the preferred tumor markers to be used in the diagnosis and follow-up of operated cases of pancreatic cancer. Testing of a panel of multiple serum tumor markers may increase the sensitivity and specificity in the diagnosis of pancreatic cancer.