Zhengjun Qiu

Effects of IL-6 and AG490 on regulation of Stat3 signaling pathway and invasion of human pancreatic cancer cells in vitro

BackgroundSignal transducer and activator of transcription 3 (Stat3) is a member of the Janus-activated kinase(Jak)/Stat signaling pathway. Abnormal activation of Stat3 plays a critical role in metastasis and invasion in varieties of human tumors including pancreatic cancer. This study aimed to investigate the mechanisms of activation and blocking of the Stat3 signaling pathway and its effects on invasion and metastasis of human pancreatic cancer cells.MethodsThe Jak inhibitor AG490 and interleukin-6 (IL-6) were added to the culture media of human pancreatic cancer cells SW1990 and Capan-2, respectively. Cell growth was measured by MTT assays. Western blotting and immunocytochemistry were performed to detect phosphorylated Stat3 (p-Stat3) protein, while VEGF and MMP-2 mRNA and protein expression were examined with fluorescence quantitative polymerase chain reaction and Western blotting, respectively. The invasion ability of SW1990 and Capan-2 cells was determined by cell invasion assay.ResultsStat3 was activated by IL-6 in Capan-2 cells; protein expression of p-Stat3 was increased significantly in Capan-2 cells. IL-6 remarkably promoted the growth of Capan-2 cells (P < 0.05), and VEGF and MMP-2 mRNA and protein expression were increased significantly. Also, IL-6 increased the invasion ability of Capan-2 cells. AG490 inhibited Stat3 activation in SW1990 cells. Western blotting and immunocytochemistry analysis showed that p-Stat3 protein expression was decreased significantly with AG490 treatment in SW1990 cells. AG490 remarkably inhibited the growth of Capan-2 cells (P < 0.05), and VEGF and MMP-2 mRNA and protein expression was decreased significantly. And AG490 decreased the invasion ability of SW1990 cells.ConclusionsAbnormal activation of Stat3 plays an important role in the invasion and metastasis of pancreatic cancer. Activation and blocking of the Stat3 signaling pathway can affect invasion ability and expression of the VEGF and MMP-2 genes in pancreatic cancer cells. The Stat3 signaling pathway may provide a novel therapeutic target for treatment of pancreatic cancer.

RNA interference-mediated signal transducers and activators of transcription 3 gene silencing inhibits invasion and metastasis of human pancreatic cancer cells

Signal transducers and activators of transcription‐3 (STAT3), a central cytoplasmic transcription factor, is frequently overexpressed and constitutively activated by tyrosine during malignant transformation. The overexpression and phosphorylation of STAT3 in pancreatic cancer has been described only recently, but the roles and mechanism still remain unclear. In this study, we elucidate the significance of the STAT3 signaling pathway in metastatic potentials of pancreatic cancer. We stably silence the expression of the STAT3 and p‐STAT3 by using RNA interference (RNAi) in the pancreatic cancer cell line SW1990, and then reduce its invasion capacity in vitro and metastasis capacity in vivo compared to parental cells or cells tansfected with a control vector. Furthermore, silencing SW1990 cells with the STAT3 gene by RNAi also led to a decrease of matrix metalloproteinases‐2 (MMP‐2) and vascular endothelial growth factor (VEGF) at the mRNA and protein level. Collectively, these studies suggest that activation of the STAT3 signaling pathway plays an important role in the progression of pancreatic cancer, and that silence of the STAT3 gene with RNAi may be a useful anti‐invasive therapeutic option in pancreatic cancer. (Cancer Sci 2007; 98: 1099–1106)

Regulation of miR-155 affects pancreatic cancer cell invasiveness and migration by modulating the STAT3 signaling pathway through SOCS1.

In the present study, we investigated the effects of miR-155 on pancreatic cancer cell invasion and migration in vitro, underlying gene expression, expression of miR-155 and its target genes in pancreatic cancer tissues, and their association with metastasis and clinical stage. miR-155 mimics and an inhibitor were transfected into Panc-1 and Capan-2 cells in order to regulate the expression of miR-155. qPCR and western immunoblotting were performed in order to detect gene expression. Transwell assays were performed to characterize the invasion and migration of pancreatic cancer cells in vitro. Immunohistochemical analysis and in situ hybridization were used to detect the expression of protein and microRNA in pancreatic cancer tissue. miR-155 mimics and an inhibitor upregulated and downregulated, respectively, the expression of miR-155 in pancreatic cancer cells. The invasion and migration of pancreatic cancer cells increased or decreased along with miR-155 expression in vitro. Suppressor of cytokine signaling 1 (SOCS1) protein expression was upregulated when miR-155 was inhibited and downregulated when miR-155 was increased. However, the expression of P-signal transducer and activator of transcription-3 (STAT3) was synchronized with that of miR-155. Transcription of SOCS1 and STAT3 was unchanged by miR-155 regulation. miR-155 expression was high in pancreatic cancer tissues and SOCS1 expression was high in tumor-adjacent tissues. There was no relationship between these genes in cancer and tumor-adjacent tissues. In addition, miR-155 expression was associated with lymph node metastasis and clinical stage. In conclusion, miR-155 plays an important role in the regulation of pancreatic cancer cell invasion and migration by modulating the STAT3 signaling pathway and reducing SOCS1 expression in pancreatic cancer cells.

Laparoscopic and open resection for colorectal cancer: an evaluation of cellular immunity

BackgroundColorectal cancer is one kind of frequent malignant tumors of the digestive tract which gets high morbidity and mortality allover the world. Despite the promising clinical results recently, less information is available regarding the perioperative immunological effects of laparoscopic surgery when compared with the open surgery. This study aimed to compare the cellular immune responses of patients who underwent laparoscopic(LCR) and open resections(OCR) for colorectal cancer.MethodsBetween Mar 2009 and Sep 2009, 35 patients with colorectal carcinoma underwent LCR by laparoscopic surgeon. These patients were compared with 33 cases underwent conventional OCR by colorectal surgeon. Clinical data about the patients were collected prospectively. Comparison of the operative details and postoperative outcomes between laparoscopic and open resection was performed. Peripheral venous blood samples from these 68 patients were taken prior to surgery as well as on postoperative days(POD) 1, 4 and 7. Cell counts of total white blood cells, neutrophils, lymphocyte subpopulations, natural killer(NK) cells as well as CRP were determined by blood counting instrument, flow cytometry and hematology analyzer.ResultsThere was no difference in the age, gender and tumor status between the two groups. The operating time was a little longer in the laparoscopic group (P > 0.05), but the blood loss was less (P = 0.039). Patients with laparoscopic resection had earlier return of bowel function and earlier resumption of diet as well as shorter median hospital stay (P < 0.001). Compared with OCR group, cell numbers of total lymphocytes, CD4+T cells and CD8+T cells were significant more in LCR group (P < 0.05) on POD 4, while there was no difference in the CD45RO+T or NK cell numbers between the two groups. Cellular immune responds were similar between the two groups on POD1 and POD7.ConclusionsLaparoscopic colorectal resection gets less surgery stress and short-term advantages compared with open resection. Cellular immune respond appears to be less affected by laparoscopic colorectal resection when compared with open resection.

Short-term and medium-term clinical outcomes of laparoscopic-assisted and open surgery for colorectal cancer: a single center retrospective case-control study

BackgroundLaparoscopic procedure is a rapid developed technique in colorectal surgery. In this investigation we aim at assessing the diversities of short-term and medium-term clinical outcomes of laparoscopic-assisted versus open surgery for colorectal cancer.MethodsA total number of 519 patients with non-metastatic colorectal cancer were enrolled for this study. The patients underwent either laparoscopic-assisted surgery (LAP) (n = 254) or open surgery (OP) (n = 265). Surgical techniques, perioperative managements and clinical follow-ups were standardized. Short-term perioperative data and medium-term recurrence and survival were compared and analyzed between the two groups.ResultsThere were no differences in perioperative parameters between the two groups except in regards to a trend of faster recovery in laparoscopic procedures. There was no statistically significant difference in postoperative complications, reoperation rate, or perioperative mortality. Statistically significant differences in a faster return of gastrointestinal function and shorter hospital stay were identified in favor of laparoscopic-assisted resection. In colon and rectal cancer cases separately, the overall survival, cancer-free survival and recurrence rate were similar in two groups. There was also no tendency of significant differences in overall survival, cancer-free survival and recurrence in stage I-II and stage III patients in two cancer categories between the two groups, respectively. pT, lymph node metastasis, and clinical stage were independent predictors of overall death risk, while pT, pN, lymph node metastasis and clinical stage were found to be the independent predictors of recurrence risk in enrolled patients database.ConclusionsLaparoscopic-assisted procedure has more benefits on postoperative recovery, while has the same effects on medium-term recurrence and survival compared with open surgery in the treatment of non-metastatic colorectal cancer.

STAT3-targeting RNA interference inhibits pancreatic cancer angiogenesis in vitro and in vivo.

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.

SMAD4 and its role in pancreatic cancer

Transforming growth factor-β (TGF-β) regulates cell functions and has key roles in pancreatic cancer development. SMAD4, as one of the Smads family of signal transducer from TGF-β, mediates pancreatic cell proliferation and apoptosis and is specifically inactivated in half of advanced pancreatic cancers. In recent years, many advances concerning SMAD4 had tried to unravel the complex signaling mechanisms of TGF-β and its dual role of tumor-suppressive and tumor-promoting efforts in pancreatic cancer initiation and progression through SMAD4-dependent TGF-β signaling and SMAD4-independent TGF-β signaling pathways. Meanwhile, its potential prognostic value based on immunohistochemical expression in surgical sample was variably reported by several studies and short of a systematic analysis. This review aimed to discuss the structure, functions, and regulation of this principal protein and its effects in determining the progression and prognosis of pancreatic cancer.

Warming with an underbody warming system reduces intraoperative hypothermia in patients undergoing laparoscopic gastrointestinal surgery: A randomized controlled study

BACKGROUND Intraoperative hypothermia is a common event during laparoscopic abdominal surgery. On one hand, intraoperative hypothermia can delay the metabolism and prevent tissue damage. One the other hand, long-term and severe intraoperative hypothermia may also lead to perioperative complications, such as increasing of peripheral resistance, coagulation dysfunction, intraoperative hemorrhage and postoperative shivering. Maintenance of normothermia during surgical procedures may improve the quality of patient care. OBJECTIVES This study investigated the feasibility and efficacy of intraoperative cutaneous warming with an underbody warming system during laparoscopic gastrointestinal surgery. METHODS 110 patients undergoing laparoscopic surgery for gastrointestinal cancer between January and December 2011 were randomized into the laparoscopic control (Control) group and laparoscopic intervention (Intervention) group. Nasopharyngeal temperature, prothrombin time, activated partial thromboplastin time, and thrombin time were measured before and during surgery, intraoperative and postoperative complications, as well as shivering after anesthesia and visual analog scale score for pain evaluation after surgery were also recorded. Clinical risk factors that may cause intraoperative hypothermia during laparoscopic surgery were also analyzed by correlation analysis. RESULTS The two groups were comparable at the baseline. Intraoperative hypothermia was observed in 29 patients (52.7%) in Control group and 3 (5.5%) in Intervention group. Nasopharyngeal temperature in Control group was significantly decreased since 30min after the start of operation until the end of surgery comparing to that at the start of anesthesia, but there was no difference in the Intervention group. In Intervention group, the nasopharyngeal temperature was remaining at ∼36.5°C, indicating the feasibility and efficiency of the underbody warming system in preventing intraoperative hypothermia during laparoscopic gastrointestinal surgery. Moreover, with anesthesia and operation time increased, there was no significant change of coagulation function, hemoglobin level as well as less intraoperative hemorrhage, less postoperative shivering and lower visual analog scale score in Intervention group comparing to Control group. Multivariate logistic regression analysis revealed that anesthesia time and volume of CO2 were independent risk factors for perioperative hypothermia. CONCLUSIONS Cutaneous warming with an underbody warming system is a feasible and effective method to prevent intraoperative hypothermia during laparoscopic gastrointestinal surgery.

Natural orifice transluminal endoscopic surgery: New minimally invasive surgery come of age

Although in the past two decades, laparoscopic surgery, considered as a great revolution in the minimally invasive surgery field, has undergone major development worldwide, another dramatic surgical revolution has quietly appeared in recent years. Ever since Kalloos first report on transgastric peritoneoscopy in a porcine model in 2004, interest in a new surgical procedure named natural orifice transluminal endoscopic surgery (NOTES) has blossomed worldwide. Considering that a NOTES procedure could theoretically avoid any abdominal incision, operation-related pain and scarring, many surgeons and endoscopists have been enthusiastic in their study of this new technique. In recent years, several NOTES studies have been carried out on porcine models and even on humans, including transvaginal cholecystectomy, transgastric appendectomy, transvaginal appendectomy, and transvesical peritoneoscopy. So what is the current situation of NOTES and how many challenges do we still face? This review discusses the current research progress in NOTES.

Down-regulation of STAT3 expression by vector-based small interfering RNA inhibits pancreatic cancer growth

AIM 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. METHODS 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. RESULTS 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. CONCLUSION 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.