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Wang X.,Fuzhou General Hospital Dongfang Hospital | Lin Y.,Fuzhou General Hospital Dongfang Hospital | Lin Y.,Fujian Provincial Hospital | Lan F.,Fuzhou General Hospital Dongfang Hospital | And 5 more authors.
Medical Oncology | Year: 2014

This study aims to examine the correlation between two single nucleotide polymorphisms (SNPs) of apoptosis-related genes and clinical outcomes in gastric cancer. A total of 221 patients with stage T2 and T3 gastric cancer treated with postoperative chemotherapy between 2003 and 2008 were retrospectively collected in this study to explore the association of rs4645878 located in BAX gene and rs1801270 located in CDKN1A gene with survival, recurrence, and toxicity to chemotherapy. Additionally, immunohistochemistry was used to detect the BAX expression in gastric cancer tissues. Patients carrying at least one variant genotype in BAX SNP (rs4645878) showed a significantly increased recurrence risk [hazard ratio (HR) 2.63; 95 % confidence internal (95 % CI) 1.71–4.03] and poor survival (HR 2.89; 95 % CI 1.88–4.44). Moreover, the recurrence and survival rate in patients with GA genotype was 72.7 and 24.7 %, respectively, compared with total recurrence rate of 54.8 %, P = 0.006, and compared with total survival rate of 46.6 %, P = 0.001. In addition, the GA genotype was related to lower BAX expression in gastric cancer tissues. The CDKN1A (rs1801270) mutant genotype was associated with a significantly decreased risk of hematologic toxicity [odds ratio (OR) 0.28; 95 % CI 0.12–0.63]. SNPs located in BAX and CDKN1A genes are closely associated with clinical outcomes in patients with gastric cancer. © 2014, Springer Science+Business Media New York.

Dang Y.,Fuzhou General Hospital Dongfang Hospital | Ouyang X.,Fuzhou General Hospital Dongfang Hospital | Wang K.,Fuzhou General Hospital Dongfang Hospital | Zhang F.,Fuzhou General Hospital Dongfang Hospital | Huang Q.,Fuzhou General Hospital Dongfang Hospital
Archives of Medical Research | Year: 2016

Background and Aims Carcinoembryonic antigen (CEA) is the most commonly used tumor marker for gastrointestinal cancers but its value for resectable gastric adenocarcinoma (RGA) patients in areas of high GA incidence is uncertain. Methods We retrospectively studied 400 subjects with RGA from the Fujian Province in China, which has a high incidence of GA. Patients had surgery between January 2010 and December 2013. CEA was measured and correlated to pathology. Results High pretreatment serum CEA (>5 ng/mL) was associated with patient age (p = 0.000), tumor size (p = 0.008), and T and N stages (p = 0.002, p = 0.032, respectively), alpha fetoprotein (p = 0.014), and CA19-9 (p = 0.000). High CEA was significantly associated with poor overall survival. Overall survival in the whole group of patients was 63.8%, whereas it was only 42.9% in the high CEA group (p = 0.0001). Mean overall survival for high CEA patients was significantly shorter than patients with low CEA (36.5 ± 2.63 months vs. 47.4 ± 0.98 months, p = 0.000). Multivariate analysis confirmed that pretreatment serum CEA was an independent prognostic factor for increased death risk. Additionally, mean CEA in 45 high CEA patients was reduced after surgery. Conclusions Pretreatment serum CEA may help to predict survival for patients with RGA in high GA incidence areas. © 2016 IMSS

Huang Q.,Fuzhou General Hospital Dongfang Hospital | Lan F.,Fuzhou General Hospital Dongfang Hospital | Zheng Z.,Fuzhou General Hospital Dongfang Hospital | Xie F.,Fuzhou General Hospital Dongfang Hospital | And 4 more authors.
Journal of Biological Chemistry | Year: 2011

Protein kinase B (Akt) plays important roles in regulation of cell growth and survival, but while many aspects of its mechanism of action are known, there are potentially additional regulatory events that remain to be discovered. Here we detected a 36-kDa protein that was co-immunoprecipitated with protein kinase Bβ (Akt2) in OVCAR-3 ovarian cancer cells. The protein was identified to be glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by MALDI-TOF/TOF MS, and the interaction of Akt2 and GAPDH was verified by reverse immunoprecipitation. Our further study showed that Akt2 may suppress GAPDH-mediated apoptosis in ovarian cancer cells. Overexpression of GAPDH increased ovarian cancer cell apoptosis induced by H 2O 2, which was inhibited by Akt2 overexpression and restored by the PI3K/Akt inhibitor wortmannin or Akt2 siRNA. Akt2 phosphorylated Thr-237 of GAPDH and decreased its nuclear translocation, an essential step for GAPDH-mediated apoptosis. The interaction between Akt2 and GAPDH may be important in ovarian cancer as immunohistochemical analysis of 10 normal and 30 cancerous ovarian tissues revealed that decreased nuclear expression of GAPDH correlated with activation (phosphorylation) of Akt2. In conclusion, our study suggests that activated Akt2 may increase ovarian cancer cell survival via inhibition of GAPDH-induced apoptosis. This effect of Akt2 is partly mediated by its phosphorylation of GAPDH at Thr-237, which results in the inhibition of GAPDH nuclear translocation. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Dang Y.,Fuzhou General Hospital Dongfang Hospital | Lan F.,Fuzhou General Hospital Dongfang Hospital | Ouyang X.,Fuzhou General Hospital Dongfang Hospital | Wang K.,Fuzhou General Hospital Dongfang Hospital | And 5 more authors.
World Journal of Surgical Oncology | Year: 2015

Background: Increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) play essential roles in the occurrence and development of human cancers, including gastric cancer (GC). However, the functional and clinical significance of lncRNAs are still poorly understood. Methods: In this study, the expression of LncRNA HNF1A antisense RNA 1 (HNF1A-AS1) was first examined by lncRNAs microarray analysis in 6 GC tissues, and was then further verified by real-time quantitative reverse transcription PCR (qRT-PCR) both in 3 GC cell lines and 161 cases of GC tissues. We also evaluated the association between HNF1A-AS1 expression and clinicopathological features of patients with GC. Results: LncRNAs microarray analysis results exhibited that HNF1A-AS1 was downregulated in GCs tissues (mean fold change 2.06, p < 0.05), which was further confirmed by qRT-PCR. The results from qRT-PCR showed that the expression of HNF1A-AS1 was not only downregulated in three GC cell lines (AGS, BGC-823, and MKN-45) relative to that in a normal gastric mucosal epithelial cell line (GES-1), but also decreased in GC tissues relative to that in paired adjacent non-neoplastic tissues (low expression, 94 of 161; low expression rate, 58.38 %). Furthermore, low HNF1A-AS1 expression was associated with tumor size/diameter (p = 0.005, multivariate analysis), levels of serum carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9), and RRM1 expression in tissue samples (p = 0.028, p = 0.009, and p = 0.006, respectively). Conclusions: Taken together, our data indicate that lncRNA HNF1A-AS1 may be a regulator of GC, and thus, it may have potential as a novel biomarker and treatment target for this type of cancer. © 2015 Dang et al.

Huang Q.,Fuzhou General Hospital Dongfang Hospital | Lan F.,Fuzhou General Hospital Dongfang Hospital | Wang X.,Fuzhou General Hospital Dongfang Hospital | Yu Y.,Fuzhou General Hospital Dongfang Hospital | And 12 more authors.
Molecular Cancer | Year: 2014

Background: Interleukin-1β (IL-1β) has been implicated in the progression of gastric adenocarcinoma (GA); however, the molecular mechanisms of action of IL-1β in GA are poorly characterized. P38 and JNK are the major MAPK family members that regulate IL-1β signaling pathways. Here, we investigated the role of both p38 and JNK in IL-1β-induced GA cell migration, invasion and metastatic potential.Methods: The effects of IL-1β-induced p38 and JNK activation in GA cells were determined using in vitro Transwell migration and invasion assays of MKN-45 and AGS cells, or an in vivo metastasis assay in nude mice. The IL-1β-induced p38 signaling pathway was further characterized in GA cells. Activation of the IL-1β/p38 signaling pathway was also assessed in human primary GA tissues by immunohistochemistry.Results: IL-1β-induced activation of p38 increased GA cell migration and invasion in vitro and promoted the metastatic potential of GA cells in vivo; these effects were attenuated by p38 siRNA or the p38 inhibitor SB202190. MMP2 or MMP9 siRNAs and the MMP2/9 inhibitor BiPS also inhibited IL-1β-induced GA cell migration and invasion in vitro. IL-1β-induced p38 activation significantly increased MMP2 and MMP9 mRNA and protein expression and activity. Luciferase reporter assays demonstrated that the activator protein-1 (AP-1) and the AP-1 binding sites of the MMP9 promoter (-670/MMP9) were activated by IL-1β-induced p38 activation. Phospho-p38 was significantly upregulated in human GA tissues (compared to matched non-neoplastic tissues), and significantly associated with lymph node metastasis, and invasion beyond the serosa. Expression of phospho-p38 significantly correlated with IL-1β, MMP2, MMP9, and c-fos expression in both human GA tissues and GA cell metastases in the lungs of nude mice. IL-1β was also capable of activating JNK in GA cells, but activation of JNK was not associated with GA cell migration and invasion. Therefore, IL-1β-induced the migration and invasion in GA cells were regulated by p38, but not by JNK.Conclusions: IL-1β-induced p38 activation and the IL-1β/p38/AP-1(c-fos)/MMP2 & MMP9 pathway play an important role in metastasis in GA; this pathway may provide a novel therapeutic target for GA. © 2014 Huang et al.; licensee BioMed Central Ltd.

Han J.,Fuzhou General Hospital Dongfang Hospital | Xie Y.,Fuzhou General Hospital Dongfang Hospital | Lan F.,Fuzhou General Hospital Dongfang Hospital | Yu Y.,Fuzhou General Hospital Dongfang Hospital | And 9 more authors.
International Journal of Oncology | Year: 2014

Growth and inflammatory factors are associated with poor prognosis in gastric adenocarcinoma (GA); however, the additive effects of growth and inflammatory factors in GA remain unclear. In this study, we investigated the ability of epidermal growth factor (EGF) and interleukin (IL-1β) to activate extracellular signal-regulated kinase (ERK)1/2 in GA cells, and correlated the relationships between their roles with the metastatic potential both in GA cells and GA tissues. The effects of EGF, IL-1β and EGF plus IL-1β in AGS and MKN-45 GA cells were examined using western blotting, Transwell migration and invasion assays, immunocytochemical staining and an activator protein (AP)-1 luciferase reporter gene assay, and was further characterized in GA tissues by immunohistochemistry. The results exhibited that EGF and IL-1β additively activated ERK1/2, increased migration and invasion than either EGF or IL-1β alone in AGS and MKN-45 cells. The mechanisms were involved in upregulating MMP-9 expression through increasing AP-1 transcriptional activity via ERK1/2 pathway; these effects were dose-dependently inhibited by silencing ERK1/2 or using U0126. In vivo data also confirmed that the overexpression of p-ERK1/2 in GA tissues correlated well with the EGF, IL-1β, EGF plus IL-1β, and was associated with metastasis, which was well correlation with the expression of MMP-9 and c-fos (AP-1). The results demonstrate that growth and inflammatory factors play an important role in metastasis of GA by additively activating ERK-1/2 and AP-1, and upregulating MMP-9. As both cytokines contribute to the migration and invasion of GA cells, EGF/IL-1β/ERK1/2 pathways may be key pathways closely associated with GA progression.

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