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Wang X.,Fuzhou General Hospital Dongfang Hospital | Lin Y.,Fuzhou General Hospital Dongfang Hospital | Lan F.,Fuzhou General Hospital Dongfang Hospital | Yu Y.,Fuzhou General Hospital Dongfang Hospital | And 4 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.

Nie X.,Fuzhou General Hospital Dongfang Hospital | Wang X.,Fuzhou General Hospital Dongfang Hospital | Lin Y.,Fuzhou General Hospital Dongfang Hospital | Yu Y.,Fuzhou General Hospital Dongfang Hospital | And 4 more authors.
Clinical Laboratory | Year: 2016

Background: Cyclin-dependent kinase inhibitor IA (CDKN1A) and Cyclin D1 (CCND1) play essential roles in the regulation of cell cycle progression and are closely associated with human cancer. CDKN1A and CCND1 single nucleotide polymorphisms (SNPs) have been demonstrated to influence the prognosis in humans with different cancers. However, their roles in the prognosis of patients with resected gastric adenocarcinoma (RGA) remain to be determined. Methods: Genotypes of CDKN1A rs1059234 and CCND1 rs603965 SNPs were performed in 235 tissue samples from RGA. The association of the genotypes of these two SNPs with the prognosis in the patients with RGA was analyzed by X2 test, multivariate Cox regression analyses, and Kaplan Meier curves. Results: During the 50 months of median follow-up time, the overall recurrence and survival rate in the whole group was 57.4% and 46.8%, respectively. Whereas, recurrence and survival rate in patients with CC genotype of rs1059234 located in 3'UTR of CDKN1A were 78.0% and 27.1% (p = 0.004; p = 0.006). Multivariate analyses further confirmed that the CC genotype was significantly related with both increased recurrence and death risk (HR 3.33, 95% CI 1.95 - 5.70; p = 1.07 × 10-5, and HR 3.45, 95% CI 1.95 - 6.10; p = 2.03 × 10-5). No significant difference among CCND1 rs603965 SNP with the prognosis was determined. Conclusions: rs1059234 of CDKN1A is closely associated with the prognosis in patients with RGA.

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 13 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 10 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.

Ma L.,Institute of Laboratory Medicine | Wang X.,Institute of Laboratory Medicine | Lan F.,Institute of Laboratory Medicine | Yu Y.,Fuzhou General Hospital Dongfang Hospital | And 4 more authors.
Medical Oncology | Year: 2015

Cyclin D1 (CCND1) plays essential roles in cancer progression. In this study, CCND1 expression patterns in 211 cases of resected gastric adenocarcinoma (RGA) tissue were determined by immunohistochemistry, and the association between CCND1 expression levels and RGA prognosis was analyzed. RGA tissues displayed differential CCND1 expression (high expression, 52.1 %; n = 110, and low expression, 47.9 %; n = 101). CCND1 expression levels were related with median overall survival time (MST). MST in patients with high CCND1 expression was 43 months, whereas with low CCND1 expression it was 62 months (P = 0.013). When data were stratified by postoperative treatments and CCND1 expression levels, the MST for patients treated with fluoropyrimidine plus platinum (n = 140) was significantly longer than for those treated with fluoropyrimidine only (n = 71) in both high and low CCND1 expression groups (65.0 vs. 29.0 months, P = 0.041; and 74.5 vs. 33.0 months, P = 0.003, respectively). Cox multivariate analyses further confirmed that high CCND1 expression was related with poor prognosis in both treatment groups [hazard ratio (HR) 1.91, 95 % confidence interval (CI) 1.12–3.23; P = 0.017, and HR 2.14, 95 % CI 1.08–4.25; P = 0.029] and that fluoropyrimidine plus platinum was more effective than fluoropyrimidine only in high CCND1 (HR 0.47, 95 % CI 0.28–0.78; P = 0.004) and low CCND1 (HR 0.44; 95 % CI 0.23–0.82; P = 0.01) expression patients. Therefore, CCND1 may be used as a prognostic biomarker for patients with RGA. © 2014, Springer Science+Business Media New York.

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