Yaozong Yuan

Dietary Fiber Intake Reduces Risk for Colorectal Adenoma: A Meta-analysis

BACKGROUND & AIMS Reports on the association between dietary fiber intake and risk of colorectal adenoma (CRA), the precursor of colorectal cancer, have been inconsistent. We conducted a meta-analysis of case-control and cohort studies to analyze this association. METHODS We searched the MEDLINE and EMBASE databases to identify relevant studies published through July 2013. A random-effects model was used to estimate summary relative risks (SRRs) and 95% confidence intervals (CIs) for associations between fiber intake and CRA risk. Heterogeneity among studies was assessed using the Cochran Q and I(2) statistics. RESULTS Our meta-analysis included 20 studies involving 10,948 subjects with CRA. The SRRs of CRA for total dietary fiber were 0.72 (95% CI, 0.63-0.83) in a high- vs low-intake analysis and 0.91 (95% CI, 0.87-0.95) per 10-g/day increase in fiber intake in a dose-response model. Subgroup analyses indicated a significant inverse association between total fiber intake and CRA risk in case-control studies (SRR, 0.66; 95% CI, 0.56-0.77), but not in cohort studies (SRR, 0.92; 95% CI, 0.76-1.10). The SRRs of CRA were 0.84 for fruit fiber (95% CI, 0.76-0.94; n = 6 studies), 0.93 for vegetable fiber (95% CI, 0.84-1.04; n = 6 studies), and 0.76 for cereal fiber (95% CI, 0.62-0.92; n = 9 studies) in high- vs low-intake analyses. CONCLUSIONS Our findings support the hypothesis that high dietary fiber intake is associated inversely with CRA risk. Further studies with prospective designs that use validated questionnaires and control for important confounders are warranted.

Pancreatic cancer incidence and outcome in relation to ABO blood groups among Han Chinese patients: a case-control study

The aim of the current study was to determine the association between ABO blood group and the risk and progression of pancreatic ductal adenocarcinoma (PDAC) in the Han Chinese ethnic group. During the period of 2000–2009, 1,431 patients with PDAC and 1,449 age‐ and sex‐matched controls were recruited in two university‐affiliated hospitals. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (ORs). The relationship between patient ABO blood group and clinicopathologic features was also analyzed. Compared with subjects having blood group O, a modestly higher risk was observed among cases with blood group A or AB with adjusted ORs (95% confidence interval) of 1.368 (1.127–1.661) and 1.391 (1.053–1.838), respectively. The TNM stages of tumors in patients with non‐O blood groups (A, B or AB) were more highly advanced than in patients with blood group O (p < 0.001). Among patients who underwent a potentially curative operation, the median survival time of patients with blood group O was significantly longer than that of patients with non‐O blood groups (16.0 months vs. 11.0 months, p = 0.001, log‐rank test). This study shows evidence of an association between blood group type and risk for development and progression of PDAC. These findings merit further confirmation in a large population‐based prospective study in patients of the Han Chinese ethnic group.

The relationship between new-onset diabetes mellitus and pancreatic cancer risk: a case-control study.

Diabetes mellitus (DM) is widely considered to be associated with pancreatic cancer, however, whether DM is a cause or consequence of pancreatic cancer is controversial. In the present study, 1458 patients with pancreatic ductal adenocarcinoma (PDAC) and 1528 age-, sex- and sociodemographic variables-matched controls were recruited in two university-affiliated hospitals from 1st January 2000 to 31st December 2009. DM was defined as fasting blood glucose (FBG) level of 7.0 mmol/L or greater. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs) and 95% confidence interval (CI). Compared with controls, a moderate increased risk of PDAC was observed among cases with long-standing diabetes (≥ 2-year duration), with an AOR (95% CI) of 2.11 (1.51-2.94). Interestingly, a significant higher risk was observed among cases with new-onset DM (<2-year duration), with an AOR of 4.43 (3.44-5.72) compared to controls without DM. In addition, we found a synergistic interaction between cigarette smoking and DM on modifying the risk of pancreatic cancer development (AOR=6.17, 95% CI 3.82-9.94). Similarly, a synergistic interaction between new-onset DM and family history of pancreatic cancer was found for pancreatic cancer risk, with an AOR (95% CI) of 11.04 (2.51-48.53). This study suggested that DM could be both an early manifestation of pancreatic cancer and an aetiologic factor. Possible effect modification on DM by family history of pancreatic cancer and smoking status should be further explored in future aetiologic studies.

DJ-1 promotes invasion and metastasis of pancreatic cancer cells by activating SRC/ERK/uPA.

A major hallmark of pancreatic ductal adenocarcinoma (PDAC) is extensive local tumor invasion and early systemic dissemination. DJ-1 has been shown to prevent cell death via the Akt pathway, thereby playing an important role in cancer progression and Parkinsons disease development. Here, we investigated the role of DJ-1 in tumor invasion and metastasis of pancreatic cancer and showed that DJ-1 is upregulated in 68.5% of pancreatic cancer specimens, correlated with tumor stage and predictive of short overall survival. Knockdown of DJ-1 expression in two PDAC cell lines reduced cell migration and invasion potential in vitro and inhibited metastasis in vivo. Knockdown of DJ-1 led to cytoskeleton disruption and diminished urokinase plasminogen activator (uPA) activity and expression, without affecting plasminogen activator inhibitor-1 and uPA receptor (uPAR) expression. All these effects were reversed by restoration of DJ-1 expression. In determining the pathway through which DJ-1 regulated cell migration and invasion, DJ-1 was found not to regulate Akt phosphorylation. Rather, it promoted extracellular signal-regulated kinase (ERK) and SRC phosphorylation. Inhibition of the ERK pathway in PDAC mimicked the effects of DJ-1 on cell migration, invasion, actin cytoskeleton and uPA/uPAR system and abolished the effects on promoting PDAC cell invasion and migration. These data represent the first identification of an important function of DJ-1, which is to regulate the invasion and metastasis properties of PDAC through the ERK/uPA cascade.

Metformin alters the expression profiles of microRNAs in human pancreatic cancer cells

AIMS To investigate the effect of metformin on the expression profiles of microRNAs in human pancreatic cancer cells. METHODS MicroRNAs real-time PCR Array was applied to investigate differentially expressed miRNAs in Sw1990 cells treated with or without metformin. Stem-loop real time RT-PCR was used to confirm the results of the array assay in Sw1990 and Panc-1 cells. The effects of miR-26a on cell growth, apoptosis, invasion and migration abilities were respectively examined by CCK8 assay, Apoptosis assay, Matrigel invasion and migration assay. HMGA1 was proved to be a target of miR-26a by Luciferase reporter assay, Real-time PCR and Western-blotting. RESULTS Nine miRNAs were significantly up-regulated in metformin treated cells. Metformin up-regulated the expression of miR-26a, miR-192 and let-7c in a dose-dependent manner. Forced expression of miR-26a significantly inhibited cell proliferation, invasion, migration and increased cell apoptosis, whereas knockdown of miR-26a obtained the opposite effect. Furthermore, we demonstrated that HMGA1, an oncogene, is a direct target of miR-26a. Nude mice xenograft models confirmed that metformin up-regulated the level of miR-26a and surpressed the expression of HMGA1 in vivo. CONCLUSION These observations suggested that modulation of miRNA expression may be an important mechanism underlying the biological effects of metformin.

XAF1 as a prognostic biomarker and therapeutic target in pancreatic cancer

XAF1 (X chromosome‐linked inhibitor of apoptosis [XIAP]‐associated factor 1) is a novel XIAP modulator that negatively regulates the anti‐apoptotic effects of XIAP and sensitizes cells to other cell death triggers. It has been reported to be downregulated in a variety of human cancer cell lines. However, the role of XAF1 in pancreatic carcinogenesis remains unclear. In the present study, we investigated the prognostic values of XAF1 expression and its regulation in cancer cell growth and apoptosis both in vitro and in vivo. From the immunohistochemistry staining of tissue microarray, 40 of 89 (44.9%) pancreatic specimens showed low levels of XAF1 expression. Statistical analysis suggested the downregulation of XAF1 was significantly correlated with tumor staging (P = 0.047) and those patients with low XAF1 levels had shorter survival times (P = 0.0162). Multivariate analysis indicated that XAF1 expression was an independent prognostic indicator of the survival of patients with pancreatic cancer (P = 0.007). Furthermore, we found that restoration of XAF1 expression mediated by Ad5/F35 virus suppressed cell proliferation and induced cell cycle arrest and apoptosis, accompanied by the activation of caspases 3, 8, and 9 and poly(ADP‐ribose) polymerase as well as increased level of cytochrome c and Bid cleavage. Notably, XAF1 restoration robustly decreased survivin expression rather than XIAP. In addition, in vivo s.c. xenografts from Ad5/F35‐XAF1 treatment, which showed less cellular proliferation and enhanced apoptosis, were significantly smaller than those from control groups. Our findings document that XAF1 is a valuable prognostic marker in pancreatic cancer and could be a potential candidate for cancer gene therapy. (Cancer Sci 2009)

Activated protein C, an anticoagulant polypeptide, ameliorates severe acute pancreatitis via regulation of mitogen-activated protein kinases

BackgroundOur aim was to investigate the changes of mitogen-activated protein kinases (MAPKs) by activated protein C (APC) treatment in rats with severe acute pancreatitis (SAP), and relate them to changes in SAP severity, thus providing evidence for developing clinical therapies.MethodsSprague-Dawley rats were given an intravenous injection of saline (SAP group), APC (50 µg/kg or 10 µg/kg), or CNI1493 just before SAP induction. One group of rats underwent a sham operation (control group). Experimental samples were harvested 16 h after SAP induction. The gene expression of pancreatic MAPKs was evaluated by cDNA microarrays. The mRNA and protein/phosphorylated protein levels of p38 MAPK, extracellular signal-regulated protein kinase (ERK) 1/2, and c-Jun N-terminal kinase (JNK) and the protein levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were determined in pancreatic tissue. The severity of disease was evaluated by pancreatic histology, the pancreatic wet/dry weight ratio, and the serum amylase level.ResultsIn rats treated with APC (50 µg/kg) or CNI1493, the severity of pancreatitis and expression of pancreatic TNF-α and IL-1β proteins were attenuated by the decreased expression and activity of p38 MAPK and JNK (vs. the SAP group, P < 0.01). The expression and activity of ERK1/2 were increased in APC-treated rats, especially in the group treated with APC 50 µg/kg (vs. the SAP or CNI1493-treated group, P < 0.01, respectively).ConclusionsInhibition of expression of pancreatic p38 MAPK and JNK and upregulation of ERK1/2 expression by APC treatment may protect against pancreatic injury, thus ameliorating severity of the disease.

Upregulation of REG Iα accelerates tumor progression in pancreatic cancer with diabetes

Diabetes is now generally accepted as a crucial event in the process of pancreatic cancer (PaC). However, molecular mechanisms underlying the relationship between diabetes and PaC are not fully understood. Regenerating gene (REG) Iα is a growth factor affecting pancreatic islet beta cells, and it has been shown to be involved in the carcinogenesis in gastrointestinal tract. It is rational to speculate that REG Iα plays a potential role in the pathogenesis of PaC with diabetes. The aim of this study was to evaluate the REG Iα protein expression profile in PaC with and without diabetes, and define the contribution of REG Iα on PaC development. We found that REG Iα protein preferentially expressed in cancerous tissues of PaC patients with diabetes by Western blot. REG Iα positive cancer cells in PaC with diabetes (n = 38) was significantly higher than that in subjects without diabetes (n = 42, p < 0.05) by immunohistochemical analysis. Furthermore, we found that overexpression of REG Iα protein in PaC cell lines resulted in accelerated cell proliferation and consequently tumor growth, both in vitro and in vivo. The findings suggest that REG Iα may act as one of the tumor promoter and contribute to the aggressive nature of PaC, especially in the subpopulation with diabetes. This study would shed new insights for understanding the molecular mechanisms underlying the link between diabetes and PaC.

Voltage-Gated Potassium Channels in IB4-Positive Colonic Sensory Neurons Mediate Visceral Hypersensitivity in the Rat

OBJECTIVES:Irritable bowel syndrome (IBS) is associated with a state of chronic visceral hypersensitivity, but the underlying molecular mechanisms of visceral hyperalgesia remain elusive. This study was designed to examine changes in the excitability and alterations of voltage-gated K+ currents in subpopulations of colonic dorsal root ganglion (DRG) neurons in a rat model of IBS-like visceral hypersensitivity.METHODS:The model of IBS-like visceral hypersensitivity was induced by intracolonic infusion of 0.5% acetic acid (AA) in saline from postnatal days 8 –21. Experiments were conducted when rats became adults. DRG neurons innervating the colon were identified by 1,1′-dioleoyl-3,3,3′,3-tetramethylindocarbocyanine methanesulfonate (DiI) fluorescence labeling and were immunostained for isolectin B4 (IB4) binding to classify these colonic neurons. Patch-clamp recordings were made from acutely dissociated DiI-labeled DRG neurons, and the expression of K+ channel in L6-S2 DRG was examined by reverse transcription–polymerase chain reaction (RT-PCR) and western blot.RESULTS:(1) Neonatal AA treatment induced long-lasting visceral hypersensitivity without significant inflammation but with mast cell hyperplasia. (2) Colonic DRG neurons contained IB4-positive and negative neurons with different electrophysiological properties. IB4-positive colonic neurons have longer action potentials (APs) and larger A-type K+ currents (IA) than the IB4-negative neurons, and IB4 phenotypic changes of colonic neurons were not involved in the chronic visceral hypersensitivity. (3) Neonatal AA treatment decreased IA density and changed the electrophysiological properties of IA and IK by shifting the steady-state inactivation toward a negative direction in IB4-positive colonic neurons. The excitability of these cells increased. (4) Kv4.3 was downregulated in neonatal AA-treated rats compared with control rats, which suggests a possible mechanism regarding the changes in electrical activity of DRG neurons in these rats.CONCLUSIONS:A new model for chronic visceral hypersensitivity following a diluted AA stimulus in the neonatal period is described. The hypersensitivity may be associated with mast cell hyperplasia in the colon and increased excitability of IB4-positive colonic neurons as a result of suppression of IA density and a shift in the inactivation curves of IA and IK in a hyperpolarizing direction in these cells. This study identifies for the first time a specific molecular mechanism in subpopulations of colonic DRG neurons that underlies chronic visceral hypersensitivity.

Validation of the pretreatment neutrophil-lymphocyte ratio as a predictor of overall survival in a cohort of patients with pancreatic ductal adenocarcinoma.

Objectives The circulating neutrophil-lymphocyte ratio (NLR) has been shown to be a prognostic factor for a variety of tumors. In this study, we evaluated the prognostic significance of NLR in a large cohort of Chinese patients with pancreatic ductal adenocarcinomas (PDACs). Methods A total of 381 patients with PDAC who underwent potentially curative surgery were recruited from 2 centers in Shanghai, China, between January 2004 and September 2011. Analysis of overall survival (OS) was performed using the Kaplan-Meier and log-rank tests and the Cox proportional hazards regression model. Results The most optimal cutoff of NLR was NLR 2.0 or greater, and the NLR was divided into 2 groups: high (≥2.0) and low (<2.0). The high NLR (≥2.0) was associated with advanced UICC (Union for International Cancer Control) stages, p T stage, lymphoid node invasion, and poorer tumor differentiation. Multivariate analysis identified increased NLR as an independent prognostic factor for OS (hazard ratio = 1.51; 95 % confidence interval, 1.15–1.99; P = 0.003). Furthermore, neutrophil counts rather than lymphocyte counts were associated with OS of PDAC. Conclusions The pretreatment NLR is a simple and useful potential biomarker for OS in patients with PDAC after curative resection.