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To elucidate the mechanism of action of HOXA11-AS in modulating the cisplatin resistance of nasopharyngeal carcinoma (NPC) cells. HOXA11-AS and miR-454-3p expression in NPC tissue and cisplatin-resistant NPC cells were measured via quantitative reverse transcriptase polymerase chain reaction. NPC parental cells (C666-1 and HNE1) and cisplatin-resistant cells (C666-1/DDP and HNE1/DDP) were transfected and divided into different groups, after which the MTT method was used to determine the inhibitory concentration 50 (IC50) of cells treated with different concentrations of cisplatin. Additionally, a clone formation assay, flow cytometry and Western blotting were used to detect DDP-induced changes. Thereafter, xenograft mouse models were constructed to verify the in vitro results. Obviously elevated HOXA11-AS and reduced miR-454-3p were found in NPC tissue and cisplatin-resistant NPC cells. Compared to the control cells, cells in the si-HOXA11-AS group showed sharp decreases in cell viability and IC50, and these results were reversed in the miR-454-3p inhibitor group. Furthermore, HOXA11-AS targeted miR-454-3p, which further targeted c-Met. In comparison with cells in the control group, HNE1/DDP and C666-1/DDP cells in the si-HOXA11-AS group demonstrated fewer colonies, with an increase in the apoptotic rate, while the expression levels of c-Met, p-Akt/Akt and p-mTOR/mTOR decreased. Moreover, the si-HOXA11-AS-induced enhancement in sensitivity to cisplatin was abolished by miR-454-3p inhibitor transfection. The in vivo experiment showed that DDP in combination with si-HOXA11-AS treatment could inhibit the growth of xenograft tumors. Silencing HOXA11-AS can inhibit the c-Met/AKT/mTOR pathway by specifically upregulating miR-454-3p, thus promoting cell apoptosis and enhancing the sensitivity of cisplatin-resistant NPC cells to cisplatin.

Thrombospondin-1 plays an important role in cancer development and progression. This study investigated if a correlation exists between single-nucleotide polymorphisms (SNPs) in the Thrombospondin-1 gene (THBS1) and gastric cancer. We conducted a case-control study on a randomly recruited population of 283 patients and 283 healthy individuals from the city of Fuzhou in Southeast China. Individuals were genotyped for four SNPs (rs1478604 AG, rs2228261 CT, rs2292305 TC, and rs3743125 CT) in THBS1 using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. THBS1 genotypic distributions between the case and control groups were tested for correlations with cancer development. Comparisons between the case and control groups showed no significant differences in the genotypic distributions of rs1478604 AG, rs2228261 CT, and rs3743125 CT. However, we found a statistically significant association between homozygous CC of THBS1 rs2292305 TC and development of highly differentiated carcinoma (HDC). The rs1478604 AG variant was found to be associated with invasion and lymph node metastasis in gastric cancer. After logistic regression and stratification analysis, rs1478604 AG was more strongly associated with lymph node metastasis in HDC gastric cancer. The power to detect an effect for rs1478604 AG in HDC was 90%. These findings indicate that the THBS1 rs1478604 AG variant is linked with differential risks for gastric cancer nodal metastasis. These results support further investigation of THBS1 as a potential therapeutic target in gastric cancer.

Background and Objectives The roles of thrombospondin-1 (THBS-1) in tumor growth and metastasis are complicated and its function as a cancer inhibitor or promoter remains controversial. This clinical study investigated the functional roles of THBS-1 in gastric carcinoma by examining the expression patterns of THBS-1 protein and mRNA levels during gastric cancer development. Methods Eighty-two gastric carcinomas were included in this study. THBS-1, α-smooth muscle actin, and CD34 proteins were localized by immunohistochemical staining, and the levels of THBS-1 mRNA were quantified by real-time polymerase chain reaction. Results THBS-1 mRNA expression in gastric carcinoma tissues was significantly higher than in adjacent non-cancerous stomach tissues (P = 0.03). Tumor THBS-1 mRNA expression level was significantly related to lymph node metastasis (P = 0.031), tumor size (P = 0.021) and patient age (P = 0.005). THBS-1 protein was mainly located in stromal myofibroblasts, and was undetectable in tumor cells. Myofibroblasts may be mainly derived from stromal fibroblasts in gastric cancer. The abundance of myofibroblasts was positively correlated with tumor growth and nodal metastasis in gastric carcinoma (P = 0.03, P = 0.0008, respectively). Conclusions This clinical study revealed that overexpression of THBS-1 in stromal myofibroblasts is associated with tumor growth and nodal metastasis in gastric carcinoma. THBS-1 may activate latent transforming growth factor-β1 to stimulate fibroblasts to differentiate into myofibroblasts, though further studies are needed to validate this hypothesis. These results suggest that THBS-1 and myofibroblasts may serve as novel targets for strategies aimed at protection against and treatment of gastric carcinoma. J. Surg. Oncol. 2012; 106:94–100. © 2012 Wiley Periodicals, Inc.

A MYCL1 single nucleotide polymorphism, rs3134613, has been reported to play an important role in many cancers. However, its involvement in gastric cancer is controversial. The aim of the study was to investigate the influence of rs3134613 on the development and progression of gastric cancer in a southeast Chinese population. Genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism in 317 gastric cancer patients and 200 cancer-free controls. Data show that the risk of diffuse-type gastric cancer in carriers with the T allele (T/T or G/T genotype) was higher than that in carriers with the G/G genotype (adjusted odds ratio [OR] = 2.601, 95% confidence interval [CI] = 1.431-4.895, p = 0.003). The risk of diffuse-type gastric cancer in T allele carriers was higher than that in G allele carriers (adjusted OR = 1.594, 95% CI = 1.157-2.286, p = 0.009). The risk of poorly differentiated cancer in carriers with the T allele (T/T or G/T genotype) was higher than that in carriers with the G/G genotype (adjusted OR = 1.963, 95% CI = 1.156-3.325, p = 0.015). The results demonstrate that rs3134613 is associated with susceptibility to diffuse-type gastric cancer and with differentiation of gastric cancer. rs3134613 may be used as a potential marker to identify individuals who are at high risk of diffuse-type gastric cancer.

To investigate the effect of PC cell-derived growth factor (PCDGF) RNA interference on esophageal squamous carcinoma cells Eca-109 in vitro.The PCDGF-shRNA expression vector was transfected into the Eca-109 cells by liposome. After transfection, the mRNA and protein expressions of PCDGF were detected by RT-PCR and Western-blot respectively. Cell Counting Kit-8 (CCK-8) assay and Boyden chamber method were performed to measure the cell proliferation and invasion ability respectively.The expression levels of PCDGF mRNA and protein were both decreased in Eca-109 cells transfected with PCDGF-shRNA expression vector (transfection group). Twenty-four, 48 and 72 h after transfection, the cells proliferation in the transfection group was inhibited, and the inhibition rate was 20.4%, 21.1% and 20.9% respectively. The cell proliferation activity in the transfection group was significantly lower than that in the non-transfection group, liposome group and negative vector group (all P0.05). The number of cell migration in the non-transfection group,negative vector group, liposome group and transfection group was 118.8±12.0, 100.8±9.0, 114.3±4.7, and 53.5±16.3 respectively. The differences were statistically significant between the transfection group and the other 3 groups (all P0.05).PCDGF RNA interference can inhibit the proliferation and invasion abilities of esophageal squamous carcinoma cells in vitro. PCDGF gene may be the new target of gene therapy.

To explore the association of polymorphisms in the region of three neighboring genes TRIT1, MYCL1 and MFSD2A with risk and clinicopathological features of gastric cancer, 19 tagging SNPs in this region were genotyped using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in a case-control study of 610 Chinese gastric cancer patients and 608 cancer-free controls. MFSD2A rs4233508 T>C CC genotype was associated with an increased risk of gastric cancer in younger patients and an increased risk of moderately/well-differentiated intestinal-type gastric cancer (adjusted odds ratio [OR], 1.74 and 1.50, respectively). TRIT1 rs11581557 T>G TG was associated with lymph node metastasis (TG versus TT/GG, adjusted OR, 1.64). MFSD2A rs12083239 GC genotype and TRIT1 rs2172362 or rs230310 homozygous genotype were associated with Lauren's classification (GC versus GG, adjusted OR, 1.69; GC versus GG/CC, adjusted OR, 1.74) and tumor site (rs2172362: CC versus CT, adjusted OR, 1.71; CC/TT versus CT, adjusted OR, 1.62; rs230310: CC versus CT, adjusted OR, 1.75; CC/TT versus CT, adjusted OR, 1.67) of gastric cancer, respectively. One TRIT1 haplotype, CCGT, was associated with lymph node metastasis and tumor site of gastric cancer (CCGT versus TTTT, adjusted OR, 1.91 and 1.55). This is believed to be the first report that several tagging SNPs and haplotypes in TRIT1, MYCL1 and MFSD2A region are significantly associated with risk and clinicopathological features of gastric cancer in a Chinese population. The findings might be useful for risk assessment and prognosis prediction of gastric cancer.

This study was to explore the correlations between genetic variants in MMP2-1306C/T, TIMP2 2379C/T, TIMP2 303G/A and the genetic susceptibility to gastric carcinoma (GC) in Fujian province, China.A case-control study was conducted. Polymorphisms of MMP2-1306C/T, TIMP2 2379C/T, TIMP2 303G/A in 479 gastric carcinoma patients and 469 cancer-free controls, frequency-matched by age and sex, were determined by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). Multivariate logistic regression analysis was used to evaluate the correlations between the polymorphisms with the susceptibility to gastric cancer. Tests for an interaction between the MMP2-1306C/T and TIMP2 2379C/T or TIMP2 303G/A were performed using the likelihood ratio test.The frequencies of GG, AG, AA of TIMP2 303G/A in gastric cancer group were 55.9% (267/478), 38.7% (185/478) and 5.4% (26/478); and those in control group were 53.1% (243/458), 36.9% (169/458) and 10.0% (46/458), which showed a significant difference between the patient and control groups (χ(2) = 7.0, P = 0.03). As compared with AA genotype, patients with GG + AG had a significantly higher risk of the cancer with OR of 1.94 (95%CI: 1.2 - 3.2). The frequencies of GG + AG and AA of TIMP2 303G/A in the muscle group were 87.5% (70/80), 12.5% (10/80), however, those in the serosa and beyond group were 96.0% (382/398), 4.0% (16/398), respectively, which showed a significant difference between the patient in muscle group and the serosa and beyond group (χ(2) = 9.32, P = 0.002). As compared with AA genotype, patients with GG + AG had a significantly higher risk in tumor invasion with OR of 3.4 (95%CI: 1.5 - 7.8). The frequencies of CC + CT, TT of TIMP2 2379C/T in the lymphoma node non-metastasis group were 93.4% (113/121), and 6.6% (8/121), but those in the lymphoma node metastasis group were 98.6% (349/354) and 1.4% (5/354), respectively, which showed a significant difference between the patient in the lymphoma node non-metastasis group and in the lymphoma node metastasis group in genotype distributions of TIMP2 2379C/T) χ(2) = 9.16, P = 0.002). As compared with TT genotype, patients with CC + CT had a significantly higher risk in lymph node metastasis with OR of 4.9 (95%CI: 1.6 - 15.3). MMP2-1306C/T genotype was not associated with tumor size, tissue differentiation, invasion, TNM nor lymph node metastasis of gastric carcinoma (χ(2)(tumor size) = 0.05, P = 0.98; χ(2)(depth of invasion) = 1.87, P = 0.39; χ(2)(histological type) = 0.55, P = 0.76; χ(2)(LN metastasis) = 0.44, P = 0.80; χ(2)(TNM) = 2.6, P = 0.28). There was no significant interaction between the polymorphisms of the two genes observed (χ(2) values were 0.98 and 0.80, P values were 0.81 and 0.85).Polymorphism of TIMP2 is significantly related with occurrence and development of GC and maybe acts as a new biomarker of GC in prognosis.

To explore the correlation of functional genetic variants in Nme1-509 CT and TGFβ1-1465 TC genes to the genetic susceptibility of gastric carcinoma in Fujian province, China.A case-control study was conducted in a population in Fujian province. The polymorphism of TGFβ1-509 CT (rs1800469), Nme1-1465 TC (rs16949649) in 273 gastric carcinoma patients and 277 cancer-free controls, frequency-matched by age and sex, were analysed by using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS). Adjusted odds ratios (OR) and 95% confidence evaluation intervals (95%CI) measured by multivariate Logistic regression analysis were adopted in studying the correlation of the gene polymorphism with the susceptibility of gastric cancer.After the adjustment using Logistic regression or the potential confounding effects of gender and age, as compared with TT+CT genotype gastric carcinoma patients, the homozygous Nme1-1465CC genotype carriers had a significantly higher risk in lymph node metastasis, with the OR of 2.5 (95%CI 0.08-2.10; P=0.029). There was no association obtained between TGFβ1-509 TC genotype with the tumor size, cell differentiation, tumor invasion and lymph node metastasis in gastric carcinoma. In the intestinal type gastric carcinoma group, when compared with the wild homozygous Nme1 TT* TGFβ1 CC, Nme1 TC* TGFβ1 TC, Nme1 TC* TGFβ1 TT and Nme1 CC* TGFβ1 TC genotype carriers, there was a significantly decrease of risk in gastric carcinogenesis of 0.42 fold (95%CI 0.54-0.94, P=0.022), 0.32 fold (95%CI 0.42-0.97, P=0.013) and 0.26 fold (95%CI 0.42-0.97, P=0.008), respectively.There is a significant relationship between polymorphism of Nme1-1465 TC and the prognosis of carcinoma of stomach. It also demonstrates that coexistence of Nme1-1465 TC and TGFβ1-509 TC genes may provide a synergistic effect of increasing the susceptibility of gastric carcinogenesis.