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ABSTRACT: To study the feasibility of chemoprevention of esophageal adenocarcinoma by celecoxib, a selective cyclooxygenase-2(COX-2) inhibitor using a rat model.
Rats were divided into 3 groups: model group, celecoxib group, and control group. The rat surgical model was established by performing a gastrojejunostomy plus an esophagojejunostomy 5 mm distal to the gastrojejunal anastomosis. Twenty-eight weeks after surgery, all the animals were sacrificed and the pathological changes in the esophagus were examined macroscopically. COX-2 expression was analyzed by immunohistochemistry. Prostaglandin E2(PGE2) level was measured by enzyme-linked immunosorbent assay(ELISA).
The incidence of Barrett's esophagus and esophageal adenocarcinoma in the model group was 84% and 57% respectively, significantly higher than those in the control group(P<0.01). The incidence of esophageal adenocarcinoma in the celecoxib-treated group was significantly lower than that in the model group(P<0.01), and no esophageal adenocarcinoma was detected in the control group. COX-2 expression was detected in 100% of reflux esophagitis, Barrett esophagus and esophageal adenocarcinoma, but not found in the normal tissue from the esophagus and the jejunum(P<0.01). The PGE2 level in the esophageal tissue in the model group was significantly higher than that in the control group(P<0.01). Rats in the celecoxib-treated group had significantly lower PGE2 level than that in the model group(P<0.01). The PGE2 levels were significantly higher in rats with cancer than those without cancer(P<0.01).
Celecoxib successfully prevents the development of esophageal adenocarcinoma in a rat surgical model with mixed reflux of acid and duodenal juice and significantly decreases the risk of Barrett esophagus developing esophageal adenocarcinoma. COX-2 maybe an effective selective target of chemoprevention for esophageal adenocarcinoma.
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 05/2012; 15(5):512-6.
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ABSTRACT: To investigate the risk factors of surgical interventions in patients with esophageal foreign bodies(EFBs).
Forty-three cases with EFBs underwent surgical interventions from January 1962 to January 2011 in Department of Thoracic Surgery at the Tangdu Hospital were enrolled in the study group. Forty three cases with EFBs who received non-surgical treatment in the same hospital and during the same period matched by gender and age(the age difference between the paired patients was 5 years or less) were selected as the control group. Clinical data including type of EFBs, duration of impaction, location of EFBs, complications associated with EFBs were collected. Univariate and multivariate conditional logistic analysis were used for risk factors analysis.
Univariate conditional logistic analysis showed that type of EFBs, duration of impaction, location of EFBs, and complications associated with EFBs were risk factors of surgical interventions in patients with EFBs(P<0.05). Further multivariate conditional logistic analysis showed that type of EFBs(sharp EFBs) was the independent factor of surgical interventions in patients with EFBs(P=0.043; OR=29.228, 95% CI:1.114-766.686).
Physician should pay more attention to patients with sharp EFBs. Whether the patients need surgical interventions or not should base on factors including duration of impaction, location of EFBs, and complications associated with EFBs.
Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery 09/2011; 14(9):709-10.
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ABSTRACT: Non-small cell lung cancer (NSCLC) cells are relatively resistant to ionizing radiation (IR). The phosphatidylinositol 3 (PI3) kinases are members of a family of lipid kinases that mediate cellular functions, including cell growth, proliferation and DNA repair, which may contribute to radioresistance. We studied whether inhibition of PI3 kinases could increase the response of NSCLC cells to γ-irradiation. The results showed that pretreatment of PI3 kinase inhibitor wortmannin dose-dependently radiosensitized NSCLC A549 and H1650 cells by inhibiting colony formation, which was due to enhanced G2/M arrest and apoptosis by wortmannin. The accelerated apoptosis was accompanied by increased loss of mitochondrial membrane potential (MMP) and cytochrome c release to the cytoplasm. In addition, wortmannin pretreatment significantly increased caspase-3 activation, which was associated with the repression of X-linked inhibitor of apoptosis protein (XIAP). The radio-sensitizing effect of wortmannin was correlated with the inhibition of phosphorylated PKB/Akt level. Furthermore, wortmannin down-regulated the expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) which is involved in DNA double stand break (DSB) repair, as a result, leading to the inhibition of DSBs rejoining, as indicated by increased level of γ-H2AX at 24 h after IR. Taken together, our results demonstrate that wortmannin acts as a powerful radiosensitizer in NSCLC cells by inhibiting PI3K/Akt survival signaling and DNA repair protein DNA-PKcs, suggesting that PI3 kinase inhibitors may represent a novel strategy for overcoming resistance to IR-induced apoptosis in NSCLC cells.
Oncology Reports 12/2010; 24(6):1683-9. · 1.84 Impact Factor
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ABSTRACT: The development and progression of esophageal cancer is associated with multiple alterations in the genome, including loss of the tumor suppressor phosphatase and tensin homolog deleted from the chromosome 10 (PTEN) gene. The purpose of this study was to determine the effects of adenovirus-mediated MMAC/PTEN expression on the growth and survival of human esophageal cancer cells in vitro and in vivo. We found that compared to control cells, overexpression of PTEN significantly suppressed growth and induced apoptosis in esophageal cancer cell lines Eca-109 and TE-1 via downregulation of Bcl-2 expression and changes in cell-cycle progression. Adenovirus PTEN also inhibited the growth of subcutaneous tumor xenografts by significantly reducing tumor size in vivo. Thus our results confirm the proposed functional role of MMAC/PTEN as a regulator of esophageal cancer progression in vivo and in vitro. PTEN might be an important biological marker and potential therapeutic target in the treatment of human esophageal cancer.
Bioscience Biotechnology and Biochemistry 04/2010; 74(4):736-40. · 1.28 Impact Factor
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ABSTRACT: Roscovitine, a cyclin-dependent kinases (CDKs) inhibitor, has been reported to have anti-tumor effects in some cancer cell lines by inducing apoptosis. However, the exact underlying mechanisms are not fully understood. Here, we report that roscovitine induces expression and cleavage of the universal CDK inhibitor p21Waf1/Cip1 in non-small cell lung cancer (NSCLC) A549 cells in a dose-dependent manner. Western blots of roscovitine-treated cells undergoing apoptosis consistently demonstrated a 15 kDa band that was not detected in control cultures. CDK2 activity and PCNA expression were repressed with increasing dose of roscovitine. Accompanying these molecular changes was a progressive arrest of G2 phase and decreasing of 5-bromo-2-deoxyuridine (Brdu) incorporation of S phase cells. Caspase-3 inhibitor z-DEVD-fmk almost completely abolished roscovitine-induced apoptosis, as well as the appearance of 15 kDa band, indicating that p21Waf1/Cip1 cleavage was mediated by caspase-3 activity. Furthermore, this band was predominant in the floating apoptotic cells, while weakened in the adherent cells which were vital and pre-apoptotic. We also showed that roscovitine induced an enhanced expression of gamma-H2AX, which was blocked by caspase-3 inhibition, suggesting that p21Waf1/Cip1 cleavage may interfere with DNA repair, leading to increased frequency of double strand breaks (DSBs) and enhanced apoptosis. Here we show, for the first time, that p21Waf1/Cip1 cleavage, which is mediated by caspase-3 activity, is involved in roscovitine-induced apoptosis.
Oncology Reports 01/2010; 23(1):239-45. · 1.84 Impact Factor
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ABSTRACT: This study was purposed to investigate the mechanism of C-reactive protein (CRP) on proliferation of U266 cells. The human multiple myeloma cell line U266 was incubated with human CRP (0, 5, 10, 20 mg/L) for 24 hours, then the proliferation level of U266 cells was detected by using blood analyser. The mRNA expressions of survivin and HSP90alpha were examined by RT-PCR. The results showed that the proliferation ratio was increased, as compared with the control group (p<0.05); furthermore, the mRNA levels of survivin and HSP90alpha were up-regulated in proportion to the increased CRP concentrations. There was significant correlation between expression of survivin and HSP90alpha (r=0.737, p<0.0001) in incubated cells. It is concluded that CRP can stimulate the proliferation of MM cells directly by up-regulating the expression of survivin and HSP90alpha in MM cells. CRP can be regarded as a potential target for MM treatment.
Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology 10/2009; 17(5):1242-5.
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ABSTRACT: To observe the effect of inhabitation of VEGF expression by RNA interference on the therapy of lung cancer and to obtain a novel strategy of lung cancer therapy by RNA interference.
A segment of VEGF-siRNA was synthesized according to the code of siRNA design. The constructed pSilencer-3.1-VEGF vectors were stably transfected into A549 cell line. Then the expression of VEGF was detected in stable transfectant A549 cell line by TR-PCR and Western blot. Meanwhile, the growth of stable transfectant A549 cell line and the angiogenesis of endothelial cells were studied. The tumor volume was detected in stable transfectant A549 bearing mice.
The expression of VEGF in stable transfectant A549 cell line was obviously inhibited by pSilencer-3.1-VEGF-2. Although it did not inhibit the growth of A549, it decreased the angiogenesis of endothelial cells. In vivo, compared with control group, the tumor in the pSilencer-3.1-VEGF-2-A549 bearing mice(P<0.05)growth was obviously at a slow, and the survival obviously lengthened in the pSilencer-3.1-VEGF-2-A549 bearing mice(P<0.05).
A pSilencer-3.1-VEGF vector has been successfully constructed. pSilencer-3.1-VEGF-2 can silence the expression of VEGF in A549. It can inhibit the angiogenesis of endothelial cells in vitro and the tumor growth and lengthen the survival of the bearing mice in vivo.
Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 04/2009; 25(4):341-3, 347.
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ABSTRACT: To explore the expression and clinical significance of P-glycoprotein (P-gp)/mdr1mRNA, multidrug resistance-associated protein (MRP) and lung resistance protein (LRP) in newly diagnosed non-Hodgkin's lymphoma.
mdr1 mRNA of in 41 patients with non-Hodgkin's lymphoma was assayed by semi-quantitative RT-PCR. The expressions of P-gp, MRP and LRP proteins in lymph node viable blasts were identified by flow cytometry. The results were compared with those obtained from control cases, and the correlation of the changes with clinical outcomes was analyzed.
(1) Among the 41 cases, the positive expression of P-gp protein was detected in 8 cases, MRP in 7 cases, LRP in 15 cases, and mdr 1 mRNA in 11 cases. (2) The P-gp and LRP levels in NHL were significantly higher than those in control group, but MRP wasn't. The P-gp over-expression was significantly associated with mdr1mRNA (r = 0.396, P = 0.01). No correlation was showed among the expressions of P-gp, MRP and LRP. (3) Patients with P-gp expression had a poorer outcome of chemotherapy than those with P-gp-negative (P = 0.005). P-gp expression was significantly associated with higher clinical stage (P = 0.046) and elevated serum lactate dehydrogenase level (P = 0.032), but not associated with malignant degree (P = 0.298). MRP had no impact on the outcome of chemotherapy (P = 0.212), and wasn't significantly associated with higher clinical stage (P = 0.369), elevated LDH (P = 0.762) and higher malignant degree (P = 0.451). Patients with LRP expression had a poorer outcome of chemotherapy than those LRP-negative (P = 0.012). LRP expression was significantly associated with higher clinical stage (P = 0.0019), elevated LDH (P = 0.02) and higher malignant degree (P = 0.01).
The data of this study indicate that P-gp and LRP expressions but not MRP expression are important in the mechanism of drug resistance associated with a poor clinical outcome in previously untreated NHL.
Zhonghua zhong liu za zhi [Chinese journal of oncology] 04/2009; 31(3):199-202.
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ABSTRACT: Roscovitine has been reported to have anti-proliferative properties and is in process of undergoing clinical trials. In addition to its intrinsic anticancer properties, it has recently been suggested that roscovitine may also enhance the activity of traditional chemo- and radio- therapies in certain cancer cell lines. The purpose of this study was to define the activity of roscovitine in increasing radiosensitivity of human non-small cell lung cancer (NSCLC) cell line A549 cells in vitro. A549 cells were exposed to ionizing radiation (IR) of gamma-ray with or without roscovitine pretreatment. Clonogenic assay was performed and cell cycle and apoptosis were analyzed by flow cytometry. Expression of PARP, Ku70 and Ku80 proteins was detected by Western blot. The active form of caspase-3 positive cells were measured by flow cytometry. Our results showed that roscovitine caused dose-dependent apoptosis in A549 cells. Pretreatment with minimally toxic concentration of roscovitine significantly radiosensitized A549 cells by inhibiting colony formation. We then examined potential mechanisms that may contribute to the enhanced radiation response induced by roscovitine. Our results showed that the combination treatment significantly induced apoptosis in A549 cells compared to roscovitine or IR treatment alone. Meanwhile, in the co-treatment group, the percentage of cells with the active form of caspase-3 was markedly increased, while roscovitine or IR alone had little effect. Roscovitine decreased S phase cells when used alone or in sequential combination with IR. Furthermore, this combination treatment blocked DNA repair process after IR, indicated by down regulation of Ku70 and Ku80 proteins, while the singly used treatment did not. Taken together, these results suggest that roscovitine has the potential to act as a radio-sensitizer in A549 cells by promoting caspase-3 activity and increasing apoptosis, affecting cell cycle distribution and impairing DNA repair process.
Journal of Radiation Research 09/2008; 49(5):541-8. · 1.68 Impact Factor
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ABSTRACT: Matrix metalloproteinase 1 (MMP1) plays an important role in the development of lung cancer. This study was to investigate the relation to associate the single nucleotide polymorphism(SNP)in MMP1 gene with the susceptibility to lung cancer in Northwestern Chinese population of Han nationality.
By using the methods of polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP), MMP1 -1607(1G>2G) polymorphisms in 150 patients with lung cancer, and 200 healthy controls were detected to evaluate the relationship between different genotypes and susceptibility of lung cancer.
Individuals with 2G/2G genotype had 1.77 fold risk suffering from lung cancer, when compared with ones with 1G/2G and 1G/1G genotypes. Smokers with 2G/2G genotype exhibited 3.20 fold elevated risk for lung cancer (OR 3.20; 95% CI 1.50-6.82).
The -1607(1G>2G) in promoter region of MMP1 is associated with susceptibility to lung cancer in Northwestern Chinese population of Han nationality. The genotype 2G/2G enhances the susceptibility to lung cancer.
Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 06/2006; 23(3):313-5.
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ABSTRACT: To investigate the effect of antisense RNA against vascular endothelial growth factor 165 (VEGF165) on human esophagus squamous cell carcinoma cell line EC109.
Eukaryotic expression vector for VEGF165 antisense RNA was constructed and identified. Recombinant plasmid was transfected into EC109 cells and the transfected EC109 cells were inoculated subcutaneously to nude mice. The biological characteristics and tumorigenicity of transfected EC109 cells were observed by in situ hybridization, laser confocal microscope, transmission electron microscopy and flow cytometry.
The eukaryotic expression vector pCEP-AVEGF165 was successfully constructed and expressed in transfected EC109 cells. The rate of VEGF165 expression dropped by 75% in transfected cells. The morphology and cell cycle of transfected EC109 cells were not affected by the antisense RNA, but the tumorigenicity and angiogenesis of transfected EC109 cells were greatly reduced in nude mice. The volume of tumors in pCEP-AVEGF165 transfected group, empty vector transfected group and control group were (820+/-112.5) mm3, (7 930+/-1 035) mm3 and (7 850+/-950) mm3, respectively. The microvessel density of the three groups were (8.5+/-1.2)/mm2, (44.3+/-9.4)/mm2 and (46.4+/-12.6)/mm2, respectively.
The angiogenesis and tumorigenicity of human esophageal squamous cell carcinoma were effectively inhibited by VEGF165 antisense RNA, which may be applied to treat solid tumor in the future.
Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 04/2004; 20(2):199-202.
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ABSTRACT: To investigate the protective role of ischemic preconditioning (IPC) during lung ischemia-reperfusion (I/R) injury and its influence on inflammatory cytokine production.
In vivo I/R injury of rabbit was induced by blocking hilum of the left lung. The wet/dry ratio of the lung, lung permeability index and neutrophils percentage in bronchoalveolar lavage fluid (BALF) were detected as indexes of the lung injury. Serum levels of tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6) and interleukin-8 (IL-8) were also detected using enzyme-linked immunosorbent assay. The protective role of IPC and its influence on inflammatory cytokine production were observed.
The wet/dry ratio of the lung, lung permeability index and neutrophils percentage in BALF of I/R group were 9.73 +/- 1.14, (41.62 +/- 5.77) x 10(-4) and (58.1 +/- 10.0)% respectively. The IPC group indexes were 6.23 +/- 0.69, (20.31 +/- 4.03) x 10(-4) and (23.8 +/- 5.2)% respectively. There was a significant difference between the two groups (P < 0.01). Serum levels of TNFalpha, IL-6 and IL-8 of I/R group were (0.9078 +/- 0.1062), (0.2137 +/- 0.0598) and (0.7211 +/- 0.0979) ng/ml respectively. The IPC group indexes were (0.7478 +/- 0.0843), (0.1271 +/- 0.0089) and (0.5903 +/- 0.0746) ng/ml respectively, significantly lower than that of I/R group (P < 0.01).
Lung IPC has a marked protection effect against I/R injury. The effect was related to its inhibition of inflammatory cytokines such as TNFalpha, IL-6 and IL-8, thus reducing activation and infiltration of neutrophils.
Zhonghua wai ke za zhi [Chinese journal of surgery] 07/2003; 41(7):545-7.
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ABSTRACT: To investigate the effect of antisense RNA to vascular endothelial growth factor165 (VEGF165) on human esophageal squamous cell carcinoma cell line EC109 and the feasibility of gene therapy for esophageal carcinoma.
By using subclone technique, the full length of VEGF165 amino acid cDNA, which was cut from pGEM-3Zf+,was cloned inversely into the eukaryotic expression vector pCEP4. The recombinant plasmid pCEP-AVEGF165 was transfected into EC109 cell with lipofectamine. After a stable transfection, dot blot, enzyme-linked immunosorbent assay (ELISA),laser confocal imaging system analysis, transmission electron microscopy and flow cytometry were performed to determine the biological characteristics of EC109 cell line before and after transfection in vitro and whether there was a reversion in the tumorigenic properties of the EC109 cell in vitro.
The eukaryotic expression vector pCEP-AVEGF165 was successfully constructed and transfected into EC109 cells. The expression of VEGF165 was significantly decreased in the transfected cells while the biological characteristics of the cells were not influenced by the expression of antisense gene. The tumorigenic and angiogenic capabilities were greatly reduced in nude mice, as demonstrated by reduced tumor end volume (820+/-112.5)mm(3) vs (7930+/-1035)mm(3) and (7850+/-950)mm(3), P<0.01) and microvessel density (average number: (8.5+/-1.2)mm(-2) vs (44.3+/-9.4)mm(-2) and (46.4+/-12.6)mm(-2), P<0.01) in comparison between experimental groups empty vector transfected group and control group.
The angiogenesis and tumorigenicity of human esophageal squamous cell carcinoma were effectively inhibited by VEGF165 antisense RNA. Antisense RNA to VEGF165 can potentially be used as an adjuvant therapy for solid tumors.
World Journal of Gastroenterology 03/2002; 8(1):44-8. · 2.47 Impact Factor
