NOV promoted the growth and migration of pancreatic cancer cells

NOV, a member of the CCN (Cyr61, CTGF and NOV) family, is involved in diverse biological processes, such as cell adhesion, proliferation and angiogenesis. However, its function in pancreatic cancer remains poorly understood. Here, we found that the expression of NOV was up-regulated in pancreatic cancer tissues. Moreover, over-expression of NOV in pancreatic cancer cells promoted cell proliferation and migration, while knock down the expression of NOV impaired the tumorigenecity of pancreatic cancer cells in vitro and in vivo. Mechanistically, NOV induced epithelial–mesenchymal transition (EMT) and regulated the expression of multiple EMT marker. Taken together, our study suggested the important role of NOV in pancreatic cancer and NOV might be an important therapeutic target.     

PDCD4促进吉西他滨诱导胰腺癌细胞凋亡的实验研究

目的:研究程序性细胞死亡因子4（programmed cell death 4,PDCD4）在吉西他滨诱导胰腺癌细胞凋亡中的作用。方法:用吉西他滨处理胰腺癌细胞PANC-1,荧光定量PCR和Western blot分别检测胰腺癌细胞中PDCD4的表达变化。PANC-1细胞感染PDCD4-pGC-Fu-GFP重组慢病毒和对照pGC-Fu-GFP重组慢病毒,荧光定量PCR和Western blot检测过表达效果。用吉西他滨处理过表达PDCD4的PANC-1细胞,MTT测定细胞增殖,克隆形成实验测定细胞克隆能力,流式细胞术测定细胞凋亡,Western blot检测细胞中剪切的Caspase-3（Cleaved Caspase-3）、剪切的Caspase-9（Cleaved Caspase-9）蛋白水平和胞浆、线粒体中细胞色素C（Cytochrome C）蛋白水平。结果:吉西他滨处理后的PANC-1细胞中PDCD4 mRNA和蛋白水平均明显升高。吉西他滨处理和过表达PDCD4的PANC-1细胞增殖、克隆形成能力明显降低,细胞凋亡率明显升高,细胞中Cleaved Caspase-3、Cleaved Caspase-9蛋白水平升高,胞浆中Cytochrome C蛋白水平也升高,线粒体中Cytochrome C蛋白水平降低。吉西他滨处理过表达PDCD4的PANC-1细胞增殖能力、克隆形成能力降低更多,细胞凋亡率更高,细胞中Cleaved Caspase-3、Cleaved Caspase-9蛋白水平也更高,胞浆中Cytochrome C蛋白水平更高,线粒体中Cytochrome C蛋白水平更低。结论:吉西他滨通过上调PDCD4表达水平激活线粒体途径诱导胰腺癌细胞凋亡。     

PEBP4 promoted the growth and migration of cancer cells in pancreatic ductal adenocarcinoma

Tumor Biology - Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignancies in the world. Numerous studies have linked the activation of AKT to the progression of PDAC....     

Netrin-1 promoted pancreatic cancer cell proliferation by upregulation of Mdm2

Netrin-1 displays proto-oncogenic activity in several cancers, which is thought to result from the ability of netrin-1 secretions to stimulate survival when bound to associated receptors. The objective of this study was to determine the role of netrin-1 in pancreatic cancer cell proliferation in vitro. Our results revealed that netrin-1 overexpression promoted while its silence inhibited two pancreatic cancer cell lines. At the molecular level, we found that netrin-1 promoted cell proliferation by upregulation of murine double minute 2 (Mdm2). As a result, p53 protein contents were reduced in cells overexpressing netrin-1. Therefore, our data suggests the presence of a previously unknown network in the proliferation and progression of pancreatic cancer cells.     

Cyclooxygenase 2 inhibitors and cancer chemoprevention

Chemoprevention is the use of natural or synthetic compounds in order to reverse, suppress or prevent the carcinogenic process. Among the many pathways dysregulated during the carcinogenic process, cyclooxygenase-2 (Cox2) seems to be one of the most promising pathways to target in order to achieve chemopreventive and anticancer effects. Indeed, Cox2 overexpression contributes to the carcinogenic by at least 5 different mechanisms including transformation of procarcinogens on carcinogens, pro-inflammatory and immunomodulatory effect, resistance to apoptosis, angiogenesis and invasion progression... This review will focus on the rationale and the ongoing research areas related to chemopreventive approaches targeting Cox2.     

Cyclooxygenase 2 inhibitors and colorectal cancer

Cyclooxygenase-2 (Cox2) is an inductible isoenzyme of cyclooxygenase undetectable in normal colonic mucosa and overexpressed in 80% colonic tumor. Several works in vitro and in vivo showed that Cox2 plays a key role in the multistep process of colorectal tumorigenesis such apoptosis inhibition of cellular proliferation and angiogenesis induction. So that Cox2 represent a potential molecular target in colorectal management and specific Cox2 inhibitors may be useful as chemopreventive as well as therapeutic agent in humans. In animals study Cox2 inhibitors was shown to be effective and in humans Cox2 inhibitors are approved by the Food and Drug Administration as an adjunct to endoscopic surveillance and surgery in patients with Familial Adenomatous Polyposis (FAP). The purpose of this article is to review the relationship between Cox2\Cox2 inhibitors and differents signaling pathways of colorectal carcinogenesis and to precise their possible molecular mechanisms of action. This work although review clinicals data of their efficacy as chemopreventive agent as well as therapeutic in the differents group at risk for colorectal cancer.     

IRF-2 is over-expressed in pancreatic cancer and promotes the growth of pancreatic cancer cells

Pancreatic cancer is one of the most malignant diseases in the world. Interferon regulator factor 2 (IRF-2), an interferon regulatory factor, has been known to act as an oncogene in distinct types of cancer. In this study, we found that the expression of IRF-2 was up-regulated in primary pancreatic cancer samples and associated with tumor size, differentiation, tumor–node–metastasis stage, and survival of the patients. In pancreatic cancer cells, knockdown on the expression of IRF-2 inhibited cell growth in the liquid culture and on the soft agar. Mechanistically, IRF-2 modulated the growth of pancreatic cancer cells through regulating proliferation and apoptosis effectors, such as cyclin D1 and BAX. Collectively, these results suggest that IRF-2 plays an important role in the tumorigenesis of pancreatic cancer and down-regulation of IRF-2 would be a new treatment target for pancreatic cancer.     

HDAC2 attenuates TRAIL-induced apoptosis of pancreatic cancer cells

Background  

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a dismal prognosis and no effective conservative therapeutic strategies. Although it is demonstrated that histone deacetylases (HDACs), especially the class I HDACs HDAC1, 2 and 3 are highly expressed in this disease, little is known about HDAC isoenzyme specific functions.     

Cyclooxygenase 2 genotypes influence prostate cancer susceptibility in Japanese Men

This study aims to evaluate the relationship between the cyclooxygenase 2 (COX2) G1195A (rs689465) polymorphism and the risk of prostate cancer in a Japanese population and the associations between COX2 polymorphisms and clinicopathological characteristics, including Gleason grade and prostate-specific antigen (PSA) grade. We recruited 134 patients with prostate cancer and 86 healthy controls matched for age and smoking status. The COX2 G1195A polymorphism status was determined by polymerase chain reaction and restriction fragment length polymorphism analysis. Genotype distributions (p?=?0.028) and allelic frequencies (p?=?0.014) differed significantly between prostate cancer and control groups in terms of the COX2 G1195A polymorphism (Pearson’s χ ² test). Logistic regression analysis of case and control outcomes showed an odds ratio between the GG and AA genotypes of 3.15 (95 % confidence interval?=?1.27–8.08, p?=?0.014), indicating an increased risk of prostate cancer associated with the AA genotype. Subset analysis revealed no significant associations between this polymorphism and clinicopathological characteristics of prostate cancer. This study demonstrated a relationship between the COX2 G1195A variant and prostate cancer risk. This polymorphism may merit further investigation as a potential genomic marker for the early detection of prostate cancer. Our results support the hypothesis that rs689465 influences susceptibility to prostate cancer; however, prostate cancer progression was not associated with rs689465 in a Japanese population.     

胃癌细胞促进网膜脂肪干细胞分化的机制研究

  目的  本实验主要研究在胃癌条件培养基（conditioned medium,CM）诱导下网膜脂肪干细胞（omental-adipose stromal cells,O-ASCs）是否能分化为癌相关成纤维细胞（carcinoma-associated fibroblasts,CAFs）,及ERK信号通路在其中的作用。  方法  通过诱导分化成骨、成脂及流式细胞鉴定O-ASCs,将O-ASCs与MGC803和SGC7901 CM共培养,通过RT-PCR和Western-blot检测O-ASCs细胞CAFs标志物α-SMA、FSP-1、vimentin,旁分泌因子VEGFA、TGFβ-1、FAP、SDF-1的表达水平。将O-ASCs分为对照组,SGC7901-CM实验组,SGC7901-CM+U0126处理组,12 h后收集细胞。Western blot检测O-ASCs细胞CAFs标志物α-SMA、FSP-1及ERK1/2、p-ERK1/2的表达水平。  结果  经鉴定原代培养出的细胞为O-ASCs,在SGC7901 CM和MGC803 CM作用下,CAFs标志物α-SMA、FSP-1、vimentin及旁分泌因子SDF-1、VEGFA、TGFβ-1、FAP表达均有明显增加（P < 0.05）。与对照组比较SGC7901-CM组α-SMA、FSP-1、p-ERK1/2表达明显增加（P < 0.05）,ERK表达未见明显变化（P > 0.05）。SGC7901-CM+U0126组与SGC7901-CM组比较,α-SMA、FSP-1及p-ERK1/2的蛋白表达水平明显降低（P < 0.05）,ERK表达变化无统计学意义（P > 0.05）。  结论  O-ASCs通过分化为CAFs及旁分泌作用参与胃癌腹膜转移,ERK信号通路在该过程中发挥了重要作用。      

JDP2 inhibits the epithelial-to-mesenchymal transition in pancreatic cancer BxPC3 cells

Pancreatic carcinoma is one of the most malignant and aggressive cancers. Increased motility and invasiveness of pancreatic cancer cells are believed to be associated with epithelial-to-mesenchymal transition (EMT). However, the molecular basis of EMT in pancreatic cancer cells is poorly understood. In this study, we examined the relationship between Jun dimerization protein 2 (JDP2), which is an AP-1 inhibitor, and EMT in human pancreatic carcinoma cells. We demonstrated that transforming growth factor-??1 (TGF-??1) promoted epidermal growth factor (EGF)-induced EMT in co-treated human pancreatic BxPC3 cells and that JDP2 overexpression reversed the EMT that was induced by co-treatment with TGF-??1 and EGF. These results suggest that EGF plays a principal role in EMT through its association with TGF-??1 in human pancreatic BxPC3 cells and that JDP2 may be a molecular target for pancreatic carcinoma intervention.     

沉默干扰素调控因子2降低胰腺癌细胞有氧糖酵解水平的实验研究

目的:研究干扰素调控因子2（interferon regulatory factor 2,IRF-2）对胰腺癌细胞有氧糖酵解水平的影响。方法:胰腺癌细胞感染含有IRF-2-shRNA的慢病毒及对照空载体病毒记为干扰组和阴性组，以不做处理的细胞作为对照组，用Realtime PCR和Western blot方法测定细胞中IRF-2水平，MTT方法测定胰腺癌细胞的增殖情况，Western blot方法测定细胞内糖酵解关键酶己糖激酶2（HK2）、丙酮酸激酶M2亚型（PKM2）蛋白、NF-κBp65（NF-κBp65亚型）、细胞核增殖抗原(Ki-67)表达水平，用试剂盒检测细胞乳酸生成及葡萄糖消耗水平，同时检测细胞中三磷酸腺苷（ATP）合成水平。结果:干扰组细胞中的IRF-2 mRNA和蛋白水平均明显低于对照组，而阴性组细胞中IRF-2 mRNA和蛋白水平与对照组比较没有明显差异。干扰组细胞的OD值明显降低，细胞中HK2、PKM2、NF-κBp65、Ki-67蛋白水平降低，同时细胞乳酸生成及葡萄糖消耗量均降低，细胞合成的ATP减少，与对照组相比，差异有统计学意义（P＜0.05）。阴性组细胞OD值、HK2蛋白水平、PKM2蛋白水平、Ki-67蛋白水平、NF-κBp65蛋白水平、乳酸生成、葡萄糖消耗量、ATP水平与对照组相比，差异均没有统计学意义（P＞0.05）。结论:沉默IRF-2抑制胰腺癌细胞中糖酵解关键酶表达，降低细胞糖酵解水平，抑制胰腺癌细胞增殖。     

SKP2 confers resistance of pancreatic cancer cells towards TRAIL-induced apoptosis

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dismal prognosis and no effective conservative therapy exists. Although the F-box protein S-phase kinase associated protein 2 (SKP2) is highly expressed and regulates cell cycle progression in PDAC, alternative SKP2 functions in PDAC are unknown. Using RNA interference we now demonstrate that SKP2 confers resistance of a subset of PDAC cell lines towards the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), but not the topoisomerase II inhibitor etoposide. We observed accelerated cleavage of the BH3-only protein Bid and augmented downregulation of cFLIPL, XIAP and MCL1 upon treatment of SKP2-depleted MiaPaCa2 cells with TRAIL. Our data disclose a novel SKP2 function in PDAC cells and therefore define SKP2 as a molecular target.     

Identification of pancreatic cancer stem cells

Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44(+)CD24(+)ESA(+) phenotype (0.2-0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44(+)CD24(+)ESA(+) cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44(+)CD24(+)ESA(+) pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44(+)CD24(+)ESA(+) pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.