[Show abstract][Hide abstract] ABSTRACT: MicroRNAs are involved in the initiation and progression of pancreatic cancer. In this study, we showed that miR-221/222 is overexpressed in pancreatic cancer. MiR-221/222 overexpression significantly promoted pancreatic cancer cell proliferation and invasion while inhibiting apoptosis. The expression of the matrix metalloproteinases (MMPs) MMP-2 and MMP-9 was increased in miR-221/222 mimic-transfected pancreatic cancer cells. Validation experiments identified TIMP-2 as a direct target of miR-221/222. These data indicate that overexpressed miR-221/222 may play an oncogenic role in pancreatic cancer by inducing the expression of MMP-2 and MMP-9, thus leading to cancer cell invasion.
[Show abstract][Hide abstract] ABSTRACT: Ginkgolic acid (GA) is a botanical drug extracted from the seed coat of Ginkgo
biloba L. with a wide range of bioactive properties, including anti-tumor effect.
However, whether GA has antitumor effect on pancreatic cancer cells and the
underlying mechanisms have yet to be investigated. In this study, we show that GA
suppressed the viability of cancer cells but has little toxicity on normal cells, e.g,
HUVEC cells. Furthermore, treatment of GA resulted in impaired colony formation,
migration, and invasion ability and increased apoptosis of cancer cells. In addition, GA
inhibited the de novo lipogenesis of cancer cells through inducing activation of AMPactivated
protein kinase (AMPK) signaling and downregulated the expression of key
enzymes (e.g. acetyl-CoA carboxylase [ACC], fatty acid synthase [FASN]) involved in
lipogenesis. Moreover, the in vivo experiment showed that GA reduced the expression
of the key enzymes involved in lipogenesis and restrained the tumor growth. Taken
together, our results suggest that GA may serve as a new candidate against tumor
growth of pancreatic cancer partially through targeting pathway driving lipogenesis.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the protective effect of polyenoylphosphatidylcholine (PPC) in rats with severe acute pancreatitis (SAP) and its mechanism.
Seventy-two clean, conventional Sprague-Dawley rats were randomly divided into 4 groups (SAP; sham operation [SO], SAP + PPC, and SO + PPC; n = 18 per group). The SAP model was induced by injecting 4% sodium taurocholate (1 mL/kg) into the biliopancreatic duct. Animals in the SO groups underwent laparotomy and biliopancreatic duct puncture without fluid injection. Polyenoylphosphatidylcholine (50 mg/kg) was injected through the penis dorsal vein. Pancreatic acinar cell membrane fluidity and pancreatic tissue calcium pump activity were measured through fluorescence polarization and quantization of phosphonium ions, whereas pancreatic tissue superoxide dismutase and malondialdehyde were detected through xanthine oxidase method and thiobarbituric acid colorimetric analysis method, respectively.
The SAP + PPC group had significantly improved pathologic pancreas; increased in pancreatic acinar cell membrane fluidity, pancreatic tissue Ca-Mg-ATPase activity, and superoxide dismutase; as well as decreased in malondialdehyde, ascites volume, and serum amylase compared with the SAP group.
Polyenoylphosphatidylcholine could reduce the damage to the pancreas through increasing pancreatic acinar cell membrane fluidity and pancreatic tissue calcium pump activity. Polyenoylphosphatidylcholine also scavenges oxygen free radicals and reduces lipid peroxide levels.
[Show abstract][Hide abstract] ABSTRACT: Perineural invasion (PNI) is considered as an alternative route for the metastatic spread of pancreatic cancer cells; however, the molecular changes leading to PNI are still poorly understood. In this study, we show that the CXCL12/CXCR4 axis plays a pivotal role in the neurotropism of pancreatic cancer cells to local peripheral nerves. Immunohistochemical staining results revealed that CXCR4 elevation correlated with PNI in 78 pancreatic cancer samples. Both in vitro and in vivo PNI models were applied to investigate the function of the CXCL12/CXCR4 signaling in PNI progression and pathogenesis. The results showed that the activation of the CXCL12/CXCR4 axis significantly increased pancreatic cancer cells invasion and promoted the outgrowth of the dorsal root ganglia. CXCL12 derived from the peripheral nerves stimulated the invasion and chemotactic migration of CXCR4-positive cancer cells in a paracrine manner, eventually leading to PNI. In vivo analyses revealed that the abrogation of the activated signaling inhibited tumor growth and invasion of the sciatic nerve toward the spinal cord. These data indicate that the CXCL12/CXCR4 axis may be a novel therapeutic target to prevent the perineural dissemination of pancreatic cancer.
[Show abstract][Hide abstract] ABSTRACT: Metastasis is the major cause for the high mortality rate of pancreatic cancer. Human embryonic stem cell (hESC) associated genes frequently correlate with malignant disease progression. Recent studies have demonstrated that the embryonic protein Nodal, which plays a critical role during embryonic development, is re-expressed in several types of tumors and promotes cancers progression. However, little is known about the role of Nodal in pancreatic cancer. Here, we show that Nodal expression is upregulated in human pancreatic cancer tissues. Moreover, Nodal expression levels correlate well with the grade of pancreatic cancer differentiation. In addition, we present clear evidence that Nodal induces signal transduction through the Smad2/3-dependent pathway in vitro. Furthermore, we show that Nodal promotes pancreatic cancer cell migration and invasion, induces epithelial-mesenchymal transition (EMT) and enhances the expression of matrix metalloproteinase-2 (MMP2) and CXC chemokine receptor 4 (CXCR4). Using an in vivo liver metastasis model of pancreatic cancer, we observed that blocking Nodal signaling activity with the small-molecule inhibitor SB431542 decreases the number and size of liver metastases. Taken together, our results suggest that Nodal overexpression induces a metastatic phenotype in pancreatic cancer cells, and that targeting Nodal signaling may be a promising therapeutic strategy for pancreatic cancer.
[Show abstract][Hide abstract] ABSTRACT: Metastasis is the major cause for the high mortality rates of pancreatic cancer. Human embryonic stem cell (hESC) associated genes frequently correlate with malignant disease progression. Recent studies have demonstrated that the embryonic protein Nodal, which plays a critical role during embryonic development, is re-expressed in several types of tumor and promotes cancers progression. However, little is known about the role of Nodal in pancreatic cancer. Here, we show that Nodal expression is upregulated in human pancreatic cancer tissues. Moreover, Nodal expression levels correlate well with the grade of pancreatic cancer differentiation. In addition, we present clear evidence that Nodal induces signal transduction through the Smad2/3-dependent pathway in vitro. Furthermore, we show that Nodal promotes pancreatic cancer cell migration and invasion, induces epithelial-mesenchymal transition (EMT) and enhances the expression of matrix metalloproteinase-2 (MMP2) and CXC chemokine receptor 4 (CXCR4). Using an in vivo liver metastasis model of pancreatic cancer, we observed that blocking Nodal signaling activity with the small-molecule inhibitor SB431542 decreases the number and size of liver metastases. Taken together, our results suggest that Nodal overexpression induces a metastatic phenotype in pancreatic cancer cells, and that targeting Nodal signaling may be a promising therapeutic strategy for pancreatic cancer.
[Show abstract][Hide abstract] ABSTRACT: Abstract Pancreatic ductal adenocarcinoma (PDAC) is a type of highly lethal malignant tumor. PDAC is locally invasive and is surrounded by a dense desmoplasia or fibrosis, which can involve adjacent vital structures. Previously, the effect of pancreatic stellate cells (PSCs) of stroma in the progression of PDAC has received more attention, and most in vitro and in vivo studies revealed that PSCs appear to confer biological aggressiveness. However, clinical trials targeting desmoplasia or PSCs showed disappointing results. Recent studies found that stromal components, especially activated PSCs, are able to inhibit the occurrence and progression of PDAC. Inhibition of the stroma or desmoplasia through genetic regulations or drugs accelerates the formation and progression of PDAC. Thus, we hypothesized that in various times and spaces, there is a balance between the tumor epithelia and stroma; once the balance is upset, the tumor traits may undergo certain changes. Therefore, finding the key changing points of this relationship to corrupt or influence it, instead of blindly inhibiting the stroma motivation or simply maintaining stroma activation, will destroy the cooperation or promote the competition and antagonism among cells. This approach may render tumors more vulnerable and thus unable to resist anti-cancer therapies.
Medical science monitor: international medical journal of experimental and clinical research 10/2014; 20:2002-6. DOI:10.12659/MSM.892523 · 1.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Pancreatic cancer is characterized by stromal desmoplasia and perineural invasion (PNI). We sought to explore the contribution of pancreatic stellate cells (PSC) activated by paracrine Sonic Hedgehog (SHH) in pancreatic cancer PNI and progression.
In this study, the expression dynamics of SHH were examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of carcinomatous and nonneoplastic pancreatic tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of PSCs activated by paracrine SHH signaling in pancreatic cancer PNI and progression.
We show that SHH overexpression in tumor cells is involved in PNI in pancreatic cancer and is an important marker of biologic activity of pancreatic cancer. Moreover, the overexpression of SHH in tumor cells activates the hedgehog pathway in PSCs in the stroma instead of activating tumor cells. These activated PSCs are essential for the promotion of pancreatic cancer cell migration along nerve axons and nerve outgrowth to pancreatic cancer cell colonies in an in vitro three-dimensional model of nerve invasion in cancer. Furthermore, the coimplantation of PSCs activated by paracrine SHH induced tumor cell invasion of the trunk and nerve dysfunction along sciatic nerves and also promoted orthotropic xenograft tumor growth, metastasis, and PNI in in vivo models.
These results establish that stromal PSCs activated by SHH paracrine signaling in pancreatic cancer cells secrete high levels of PNI-associated molecules to promote PNI in pancreatic cancer.
Clinical Cancer Research 06/2014; DOI:10.1158/1078-0432.CCR-13-3426 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: α -Mangostin, a natural product isolated from the pericarp of the mangosteen fruit, has been shown to inhibit the growth of tumor cells in various types of cancers. However, the underlying molecular mechanisms are largely unclear. Here, we report that α -mangostin suppressed the viability and epithelial-mesenchymal transition (EMT) of pancreatic cancer cells through inhibition of the PI3K/Akt pathway. Treatment of pancreatic cancer BxPc-3 and Panc-1 cells with α -mangostin resulted in loss of cell viability, accompanied by enhanced cell apoptosis, cell cycle arrest at G1 phase, and decrease of cyclin-D1. Moreover, Transwell and Matrigel invasion assays showed that α -mangostin significantly reduced the migration and invasion of pancreatic cancer cells. Consistent with these results, α -mangostin decreased the expression of MMP-2, MMP-9, N-cadherin, and vimentin and increased the expression of E-cadherin. Furthermore, we found that α -mangostin suppressed the activity of the PI3K/Akt pathway in pancreatic cancer cells as demonstrated by the reduction of the Akt phosphorylation by α -mangostin. Finally, α -mangostin significantly inhibited the growth of BxPc-3 tumor mouse xenografts. Our results suggest that α -mangostin may be potentially used as a novel adjuvant therapy or complementary alternative medicine for the management of pancreatic cancers.
[Show abstract][Hide abstract] ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by the excessive deposition of extracellular matrix (ECM) which has been thought to contribute to the malignant behaviour. However, the detailed mechanism and the contribution of excessive deposition of ECM in PDAC progression remain unclear. A better understanding of the mechanism involved in this process is essential for the design of new effective therapies. In this study, we demonstrated that pancreatic cancer cells exhibited increased proliferation and decreased apoptosis in response to type I collagen. In addition, exposed to type I collagen, PDAC cells lost the expression of E-cadherin and increased expression of mesenchymal markers, including N-cadherin and vimentin, which is correlated with enhanced cell migration and invasiveness. Conversely, the knockdown of β1-integrin abolished the effects induced by type I collagen. Further investigation revealed that type I collagen activates β1-integrin accompanied with significant up-regulation of Gli-1. siRNA specific to Gli-1 reversed the effects of type I collagen on PDAC invasion and epithelial-mesenchymal transition. These results suggest that there is cross-talk between the β1-integrin signaling pathway and the Hedgehog (HH) pathway in pancreatic cancer and the abnormal activation of the HH pathway plays a key role in the type I collagen-induced effects on pancreatic cancer.
Current cancer drug targets 04/2014; 14(5). DOI:10.2174/1568009614666140402105101 · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatic stellate cells play a role in the migration process of hepatocellular carcinoma cells. Here, we address the role of the stromal-derived factor-1/CXC chemokine receptor 4 (SDF-1/CXCR4) axis on hepatocellular carcinoma progression. The expression of the SDF-1 and the CXCR4 was determined through western blotting and real-time PCR analysis using hepatic stellate (LX02) and hepatocellular carcinoma (MHCC97, SMMC7721, Hep3B, and HepG2) cell lines depleted of CXCR4 using shRNA. The migration of hepatocellular carcinoma cells following exogenous treatment with SDF-1 or in co-culture cell systems was measured using the Transwell assay. In parallel, the expression of epithelial-mesenchymal transition (EMT) markers was also determined. We found that SDF-1 is highly expressed in the hepatic stellate cell line LX02 and that the hepatocellular carcinoma cells express high levels of CXCR4. Co-culturing hepatocellular carcinoma cells with LX02 or exogenous treatment with SDF-1 induced an EMT as shown by increased migration. In contrast, ablation of CXCR4 expression in HepG2 cells attenuated the migration of HepG2 cells and suppressed the EMT. Thus, hepatic stellate cells can promote hepatocellular carcinoma cell invasion through the SDF-1/CXCR4 axis.
[Show abstract][Hide abstract] ABSTRACT: Carcinogenesis is a complex process during which cells undergo genetic and epigenetic alterations. MicroRNAs control gene expression by negatively regulating protein-coding mRNAs. Several reports demonstrated that miR-106a is up-regulated in gastric and colorectal cancers and promotes tumor progression. In contrast, in glioma miR-106a plays the role of a tumor suppressor gene rather than an oncogene. Here we demonstrate that a high level of miR-106a expression is present in pancreatic cancer. Furthermore, our investigation shows that miR-106a has an oncogenic role in pancreatic tumorigenesis by promoting cancer cell proliferation, epithelial-mesenchymal transition and invasion by targeting TIMP-2. MiR-106a could be a critical therapeutic target in pancreatic cancer.
[Show abstract][Hide abstract] ABSTRACT: With the monomer [Zn(L-1)(H2O)] (1) complex in situ formed by the deprotonated hexadentate Salen-type Schiff-base ligand H2L1 (H2L1 = N,N'-bis(3-methoxy-salicylidene)cyclohexane-1,2-diamine) and Zn(NO3)(2) as the precursor, series of the hetero-trinuclear ZnLn(2) complexes [ZnLn(2)(L-1)(2)(L-2)(NO3)(2)Cl] (Ln = Nd, 2; Ln = Yb, 3; Ln = Er, 4 or Ln = Gd, 5) were obtained from the further reaction with LnCl(3) (Ln = Nd, Yb Er or Gd) and the second o-vanillin (HL2) ligand, respectively. The photophysical properties of complexes 2-4 showed that the characteristic near-infrared (NIR) luminescence of Ln(3+) ions with two emission centers and emissive lifetimes in microsecond ranges, was sensitized from the excited state (both (LC)-L-1 and (LC)-L-3) of mixed H2L1-HL2 ligands.
[Show abstract][Hide abstract] ABSTRACT: Aim: The stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) axis and Wingless and INT-1 (Wnt)/β-catenin pathway has been related to cancer progression. The aim of this study was to investigate the expression of CXCR4 and β-catenin in pancreatic cancer.
A total of 48 pancreatic cancer samples and 8 normal pancreatic tissues were selected to detect CXCR4 and β-catenin expression by an immunohistological technique. Spearman and Chi-square analyses were used to study the relation between the protein expression and clinical characteristics. Survival analysis was evaluated by the Kaplan-Meier product limit method.
The proportions of CXCR4 and β-catenin expression on pancreatic cancer cells were significantly higher than in normal pancreas tissues. There was a significant difference in CXRC4 expression levels, lymph node metastasis and TNM stage. Clinical Significance was observed for β-catenin expression and lymph node metastasis; Kaplan-Meier curves suggested that clinical prognosis is poor for patients expressing CXCR4. Multivariate analysis showed that CXCR4 expression was an independent prognostic factor for pancreatic cancer.
Both CXCR4 and β-catenin are abnormally expressed in pancreatic cancer. CXCR4 may be an important marker for pancreatic cancer progression.
Anticancer research 09/2013; 33(9):4103-10. · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
To investigate discriminating protein patterns and potential biomarkers in serum samples between pre/postoperative pancreatic cancer patients and healthy controls.
23 serum samples from PC patients (12 preoperative and 11 postoperative) and 76 from healthy controls were analyzed using matrix-assisted laser desorption and ionization time-of-flight mass spectrometry (MALDI-TOF MS) technique combined with magnetic beads-based weak cation-exchange chromatography (MB-WCX). ClinProTools software selected several markers that made a distinction between pancreatic cancer patients and healthy controls.
49 m/z distinctive peaks were found among the three groups, of which 33 significant peaks with a P < 0.001 were detected. Two proteins could distinguish the preoperative pancreatic cancer patients from the healthy controls. About 15 proteins may be potential biomarkers in assessment of pancreatic cancer resection.
MB-MALDI-TOF-MS method could generate serum peptidome profiles of pancreatic cancer and provide a new approach to identify potential biomarkers for diagnosis and prognosis of this malignancy.
Asian Pacific journal of cancer prevention: APJCP 07/2013; 14(7):4161-5. DOI:10.7314/APJCP.2013.14.7.4161 · 2.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Through the self-assembly of the benzimidazole-based ligand HL (HL=2-(1H-benzo[d]imidazol-2-yl)-6-methoxyphenol) with Zn(OAc)2·2H2O, Ln(NO3)3·6H2O (Ln=Nd, Yb, Er or Gd) and 4,4'-bipyridine ligand (bpy, 4,4'-bipyridine or bpe, trans-bis(4-pyridyl)ethylene), two series of Zn2Ln2-arrayed complexes [Zn2Ln2(L)4(bpy)(NO3)6] (Ln=Nd, 1; Yb, 2; Er, 3 or Gd, 4) and [Zn2Ln2(L)4(bpe)(NO3)6] (Ln=Nd, 5; Yb, 6; Er, 7 or Gd, 8) were obtained, respectively. The result of their photophysical properties shows that the characteristic near-infrared (NIR) luminescence of Nd(3+), Yb(3+) or Er(3+) ion has been sensitized from the excited state (both (1)LC and (3)LC) of the mixed HL and bipyridyl ligands in both complexes 1-3 and 5-7. Moreover, the change from bpy to bpe bridging for the fine-tuning of whole molecular conjugations, attributing to the different crossings of the two benzimidazole-based L(-) ligands, has the important influence on their NIR luminescent properties.
Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy 07/2013; 116C:102-110. DOI:10.1016/j.saa.2013.06.122 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hepatocellular carcinoma is one of the most common malignant neoplasms in the world and is the main cause of death in patients with liver cirrhosis. Surgical intervention is not suitable for majority of hepatocellular carcinoma. Investigation of the effective targeting to the tumor cells is essential for both primary tumors and metastases. Tumor specific cytotoxic T lymphocytes (CTL) have been considered to be the attractive vehicles for delivering therapeutic agents toward various tumor diseases. This study was to explore the distribution pattern of CTL carrying the lentiviral vectors with the characteristic of adenoviral E1 gene under the control of the cell activation-dependent CD40 ligand promoter (Lenti/hCD40L/E1AB). Following transduction with adenoviral vectors containing chimeric type 5 and type 35 fiber proteins (Ad5/35-TRAIL), these CTLs produced infectious virus when exposed to HepG2 cells. We assessed the therapeutic ability of CTLs using MTT, Western blot and colony formation assay. The novel CTL harboring Lenti/hCD40L/E1AB and Ad5/35-TRAIL caused proliferation inhibition and significant apoptosis in hepatocellular carcinoma cell lines. Thus, the novel CTL may be useful for the development of gene therapy approaches to hepatocellular carcinoma.
PLoS ONE 06/2013; 8(6):e66659. DOI:10.1371/journal.pone.0066659 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study sought to understand the mechanisms of attenuation of severe acute pancreatitis (SAP) by resveratrol (RES). SAP was experimentally induced in rats by injection of 4 % sodium taurocholate in the retrograde pancreatic duct. Three study groups were evaluated: Group I (sham-operated animals), Group II (SAP animals), and Group III (SAP animals treated with RES at 20 mg/kg/body weight, 5 min after induction of SAP). The study outcomes were histopathologic changes and alterations in biochemical markers: plasma renin activity and levels of angiotensin II, endothelin, and nitric oxide in plasma. Biochemical markers were evaluated at 3, 6, and 12 h after induction of SAP. SAP was associated with significant (p < 0.05) histopathologic changes (saponification spots in the intraperitoneal cavity, severe pancreatic edema, blood congestion, varying degrees of necrosis, etc.), as well as with elevation of biochemical markers in blood plasma. RES treatment significantly (p < 0.05) attenuated changes of both histopathologic and biochemical markers induced by SAP. In conclusion, this study provides evidence that RES treatment is a promising therapeutic approach to suppress microcirculatory disturbance in SAP.
[Show abstract][Hide abstract] ABSTRACT: Pancreatic cancer significantly affects the quality of life due to the severe abdominal pain. However, the underlying mechanism is not clear. This study aimed to determine the relationship between SP and pancreatic cancer perineural invasion (PNI) as well as mechanism of SP mediating pancreatic cancer PNI which cause pain in patients with pancreatic cancer. Human pancreatic cancer cells and newborn dorsal root ganglions (DRGs) were used to determine the expression of SP or NK-1R in pancreatic cancer cells and DRGs cells by QT-PCR and Western blotting. The effects of SP on pancreatic cancer cell proliferation and invasion were analyzed using MTT assay and Transwell matrigel invasion assay, respectively. Alterations in the neurotropism of pancreatic cancer cells were assessed by co-culture system which mimics the interaction of tumor/neuron in vivo. SP is not only widely distributed in the neurite outgrowth from newborn DRGs but also expressed in MIA PaCa-2 and BxPC-3 cells. NK-1R is found to be overexpressed in the pancreatic cancer cell lines examined. SP induces cancer cell proliferation and invasion as well as the expression of MMP-2 in pancreatic cancer cells; and NK-1R antagonists inhibit these effects. Furthermore, SP promotes neurite outgrowth and the migration of pancreatic cancer cell cluster to the DRGs, which is blocked by NK-1R antagonists in the co-culture model. Our results suggest that SP plays an important role in the development of pancreatic cancer metastasis and PNI; and blocking the SP/NK-1R signaling system is a novel strategy for the treatment of pancreatic cancer.
Molecular Cancer Research 01/2013; 11(3). DOI:10.1158/1541-7786.MCR-12-0609 · 4.38 Impact Factor