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ABSTRACT: To evaluate the effect of RNA interference (RNAi) mediated silence of signal transduction and activation of transcription (STAT)3 on the growth of human pancreatic cancer cells both in vitro and in vivo.
STAT3 specific shRNA was used to silence the expression of STAT3 in pancreatic cancer cell line SW1990. The anti-growth effects of RNAi against STAT3 were studied in vitro and in experimental cancer xenografts in nude mice. The potential pathways involved in STAT3 signaling were detected using reverse transcription polymerase chain reaction and western blotting.
The expression of the STAT3 was inhibited using RNAi in SW1990 cells. RNAi against STAT3 inhibited cell proliferation, induced cell apoptosis and significantly reduced the levels of CyclinD1 and Bcl-xL when compared with parental and control vector-transfected cells. In vivo experiments showed that RNAi against STAT3 inhibited the tumorigenicity of SW1990 cells and significantly suppressed tumor growth when it was directly injected into tumors.
STAT3 signaling pathway plays an important role in the progression of pancreatic cancer, and silence of STAT3 gene using RNAi technique may be a novel therapeutic option for treatment of pancreatic cancer.
World Journal of Gastroenterology 07/2011; 17(25):2992-3001. · 2.47 Impact Factor
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ABSTRACT: Signal transducers and activators of transcription 3 (STAT3) is a central cytoplasmic transcription factor that is activated by phosphorylation in response to extracellular signals and oncogenes. STAT3 regulates a number of pathways important in tumorigenesis including cell cycle progression, apoptosis, tumor angiogenesis, invasion and metastasis, and tumor cell evasion of the immune system. Our studies demonstrated that constitutively activated STAT3 plays an important role in the angiogenesis of pancreatic cancer. The objective of this study was to evaluate the potential use of RNA interference (RNAi) to knock down the STAT3 gene and the effect on angiogenesis of human pancreatic cancer cells in vitro and in vivo. We stably inhibited the expression of STAT3 and phosphorylated STAT3 (p-STAT3) using RNAi in the SW1990 pancreatic cancer cell line. Furthermore, RNAi for STAT3 inhibited STAT3-induced HUVEC cell migration and cell proliferation, and significantly suppressed the levels of secreted vascular endothelial growth factor (VEGF) and matrix metalloproteinases-2 (MMP-2) of SW1990 cells. In vivo experiments showed that RNAi for STAT3 significantly suppressed tumor growth and angiogenesis of SW1990 cells. Furthermore, silencing the STAT3 gene in SW1990 cells by RNAi also led to a decrease of VEGF and MMP-2 at the mRNA and protein levels. Collectively, these results demonstrate that the STAT3 signaling pathway plays an important role in the angiogenesis of pancreatic cancer and that knockdown of the STAT3 gene using the RNAi technique may be a novel therapeutic option for the treatment of pancreatic cancer.
International Journal of Oncology 06/2011; 38(6):1637-44. · 2.40 Impact Factor
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ABSTRACT: Transducer and activator of transcription-3 (STAT3) plays an important role in tumor cell invasion and metastasis. The aim of the present study was to investigate the effects of STAT3 knockdown in nude mouse xenografts of pancreatic cancer cells and underlying gene expression.
A STAT3 shRNA lentiviral vector was constructed and infected into SW1990 cells. qRT-PCR and western immunoblot were performed to detect gene expression. Nude mouse xenograft assays were used to assess changes in phenotypes of these stable cells in vivo. HE staining was utilized to evaluate tumor cell invasion and immunohistochemistry was performed to analyze gene expression.
STAT3 shRNA successfully silenced expression of STAT3 mRNA and protein in SW1990 cells compared to control cells. Growth rate of the STAT3-silenced tumor cells in nude mice was significantly reduced compared to in the control vector tumors and parental cells-generated tumors. Tumor invasion into the vessel and muscle were also suppressed in the STAT3-silenced tumors compared to controls. Collagen IV expression was complete and continuous surrounding the tumors of STAT3-silenced SW1990 cells, whereas collagen IV expression was incomplete and discontinuous surrounding the control tumors. Moreover, microvessel density was significantly lower in STAT3-silenced tumors than parental or control tumors of SW1990 cells. In addition, MMP-7 expression was reduced in STAT3-silenced tumors compared to parental SW1990 xenografts and controls. In contrast, expression of IL-1β and IgT7α was not altered.
These data clearly demonstrate that STAT3 plays an important role in regulation of tumor growth, invasion, and angiogenesis, which could be act by reducing MMP-7 expression in pancreatic cancer cells.
PLoS ONE 01/2011; 6(10):e25941. · 4.09 Impact Factor
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ABSTRACT: To investigate RNA interference targeting signal transducer and activator of transcription-3 (STAT3) on invasion of human pancreatic cancer cells.
We constructed three plasmids of RNA interference targeting the STAT3 gene. After LV (lentivirus)-STAT3siRNA (STAT3 small interfering RNA) the vector was transfected into the human pancreatic cell line, SW1990 and cell proliferation was measured by the MTT assay. Flow cytometry was used to assess cell cycle. Vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) mRNA and protein expression were examined by quantitative PCR and western blotting, respectively. The invasion ability of SW1990 cells was determined by cell invasion assay.
We successfully constructed the LV-STAT3siRNA lentivirus vector and proved that it can suppress expression of STAT3 gene in SW1990 cells. RNA interference of STAT3 by the LV-STAT3siRNA construct significantly inhibited the growth of SW1990 cells, in addition to significantly decreasing both VEGF and MMP-2 mRNA and protein expression. Moreover, suppression of STAT3 by LV-STAT3siRNA decreased the invasion ability of SW1990 cells.
The STAT3 signaling pathway may provide a novel therapeutic target for the treatment of pancreatic cancer since it inhibits the invasion ability of pancreatic cancer cells.
World Journal of Gastroenterology 09/2009; 15(30):3757-66. · 2.47 Impact Factor
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ABSTRACT: To investigate the effect of RNAi-mediated STAT3 gene inhibition on metastasis of human pancreatic cancer cells and its underlying mechanism.
STAT3 shRNA expression vector was constructed and transfected into SW1990 cells. STAT3 mRNA and STAT3 DNA-binding activity were examined using reverse transcription polymerase chain reaction (RT-PCR) and electrophoretic mobility shift assay (EMSA), respectively. The metastasis ability of SW1990 cells in vivo was determined in acute hematogenous metastasis model using nude mice. RT-PCR was performed to detect the mRNA expression of the MMP-2 and VEGF.
The mRNA expression of STAT3 and STAT3 DNA-binding activity were inhibited significantly by stable transfection of STAT3 shRNA expressing vectors. RNAi inhibition of STAT3 significantly suppressed the metastasis ability of SW1990 cells in vivo, and also markedly reduced the mRNA expression of MMP-2 and VEGF in SW1990 cells.
Inhibition of STAT3 by RNAi significantly inhibits the metastasis ability of pancreatic cancer cells through down-regulation of MMP-2 and VEGF, and may provide a novel strategy for preventing the metastasis of pancreatic cancer.
Zhonghua wai ke za zhi [Chinese journal of surgery] 08/2008; 46(13):1010-3.
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ABSTRACT: Traditional narrowband telemedicine cannot provide quality dynamic images. We conducted videoconferences of laparoscopic and endoscopic operations via an uncompressed video transmission technique. A superfast broadband Internet link was set up between Shanghai in the People's Republic of China and Fukuoka in Japan. Uncompressed dynamic video images of laparoscopic and endoscopic operations were transmitted by a digital video transfer system (DVTS). Seven teleconferences were conducted between June 2005 and June 2007. Of the 7 teleconferences, 5 were live surgical demonstrations and 3 were recorded video teleconsultations. Smoothness of the motion picture, sharpness of images, and clarity of sound were benefited by this form of telemedicine based upon DVTS. Telemedicine based upon DVTS is a superior choice for laparoscopic and endoscopic skill training across the borders.
Telemedicine and e-Health 07/2008; 14(5):479-85. · 1.42 Impact Factor
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ABSTRACT: The aim of this study was to assess the significance of expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and associated proteins in pancreatic ductal adenocarcinoma (PDA) and their impact on prognosis. Expression of HIF-1alpha, vascular endothelial growth factor (VEGF), glucose transporter-1 (Glut-1), survivin, CD34 and Ki-67 and apoptotic cells was demonstrated by immunohistochemistry or TUNEL in 58 PDAs and 20 normal pancreatic tissue samples. Our results show positivity of HIF-1alpha, VEGF, Glut-1 and survivin in 70.7%, 77.6%, 67.2% and 84.5% of the patients with PDA, respectively, which is significantly higher than in the normal counterparts. Expression of HIF-1alpha correlated positively with VEGF and Glut-1 expression but not with survivin. Strong HIF-1alpha expression associated with decreased apoptotic index and increased intratumoral microvessel density. Higher HIF-1alpha, VEGF and Glut-1 expression significantly associated with advanced tumor stage and lymph node metastasis. Patients with high HIF-1alpha, VEGF and Glut-1 expressing tumors had a poorer overall survival. Furthermore, Cox regression analysis showed that HIF-1alpha is a prognostic marker of borderline significance while VEGF was important in predicting poor outcome. These results suggest that over-expression of HIF-1alpha may play an important role in cancer progression through up-regulation of VEGF and Glut-1 in PDA patients. HIF-1alpha and VEGF are potential candidates for predicting survival.
International Journal of Oncology 07/2007; 30(6):1359-67. · 2.40 Impact Factor
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ABSTRACT: To investigate the effect and mechanism of blockade of STAT3 signaling pathway by JAK specific inhibitor-AG490 on invasion and metastasis of human highly metastatic pancreatic cancer line SW1990 in vitro.
AG490 was added into the culture media for SW1990 cells. The invasion ability of SW1990 cells was determined by cell invasion assay kit. Western blot was performed to detect the protein expression of the STAT3, phosphorylated STAT3 (p-STAT3), MMP-2 and VEGF. RT-PCR was performed to detect the mRNA expression of the MMP-2 and VEGF.
20 micromol/L AG490 significantly inhibited the invasion ability of SW1990 cells and the inhibitory rate of invasion ability was (77.67 +/- 7.79) %. The use of AG490 not only markedly reduced the protein expression of p-STAT3, MMP-2 and VEGF, but also greatly reduced the mRNA expression of MMP-2 and VEGF.
Blocking STAT3 activation with AG490 can inhibit the invasion and metastasis ability of pancreatic cancer cells in vitro through down-regulation of MMP-2 and VEGF expression. Blocking STAT3 signaling pathway may provide a novel strategy in prevention of invasion and metastasis of pancreatic cancer.
Zhonghua zhong liu za zhi [Chinese journal of oncology] 01/2007; 28(12):890-3.
