scholarly journals Methionine Aminopeptidase 2 as a Potential Target in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Eliana Steinberg ◽  
Rawnaq Esa ◽  
Ouri Schwob ◽  
Tali Stern ◽  
Natalie Orehov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Metastatic Cancer ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Methionine Aminopeptidase ◽  
Inhibition Of Proliferation ◽  
Expression Levels ◽  
Potential Target ◽  
Pancreatic Cancer Cells

Abstract Pancreatic ductal adenocarcinoma (PDA) is an aggressive metastatic cancer with a very low survival rate. This tumor is hypovascularized and characterized by hypoxic regions, yet they are not impeded by the oxidative stress in their microenvironment. PDA’s high resilience raises the need to find new effective therapeutic targets. This study investigated methionine aminopeptidase 2 (MetAp2) — a metallopeptidase known to play an important role in tumor progression — as a potential target for treating PDA by blocking its activity. Immunohistology of patient-derived PDA tissue sections revealed high expression of MetAp2 in metastatic regions compared with primary sites. Pancreatic cancer cells (cell lines and patient derived) exhibited high expression levels of MetAp2 and significant inhibition of proliferation upon exposure to a selective MetAp2 inhibitor. The growth of Orthoptic pancreatic PancOH7 tumors in mice was significantly suppressed when MetAp2 inhibitor was administered orally. Our finding revealed that the inhibition of MetAp2 in cells was associated with a significant reduction in glutathione (GSH) levels, a substance known for its role in alleviating oxidative stress, which suggests a possible rationale for the anti-cancer activity in highly hypoxic tumors such as PDA. Taken together, our results indicate that MetAp2 can be a studied as a target in PDA and possibly in other tumors with high expression levels of MetAp2 which are not necessarily highly angiogenic tumors.

scholarly journals DNA-Methylation-Caused Downregulation of miR-30 Contributes to the High Expression of XPO1 and the Aggressive Growth of Tumors in Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1101 ◽  
Author(s):  
Asfar S. Azmi ◽  
Yiwei Li ◽  
Amro Aboukameel ◽  
Irfana Muqbil ◽  
Philip A. Philip ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Cells ◽  
Nuclear Export ◽  
The United States ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Multiple Tumor ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with high mortality in the United States. One of the important signal transduction proteins involved in the regulation of pancreatic cancer’s aggressive progression is the nuclear export protein (XPO1). High expression of XPO1 has been found in pancreatic, lung, breast and other cancers and lymphomas with a poor prognosis of patients with tumors and high proliferative activity of cancer cells. Because XPO1 exports multiple tumor suppressor proteins simultaneously from the nucleus, the inhibition of XPO1 may retain multiple tumor suppressors in the nucleus, resulting in the suppression of cell proliferation and the induction of apoptosis in tumors. In this study, we found that the high expression of XPO1 in pancreatic cancer cells could be, in part, due to the methylation of the miR-30 gene, leading to the low expression level of the miR-30 family. By co-transfection of the XPO1 3′-UTR-Luc target vector with miR-30 mimic, we found that XPO1 is a direct target of the miR-30 family. We also observed that the enforced expression of the miR-30 family inhibited the expression of XPO1, resulting in the suppression of pancreatic cancer growth both in vitro and in vivo. These findings could help to design a novel therapeutic strategy for the treatment of pancreatic cancer by introducing miR-30 into cancer cells.

scholarly journals The role of S100A9 in the interaction between pancreatic ductal adenocarcinoma cells and stromal cells

2021 ◽  
Author(s):  
Pin-Jui Kung ◽  
Ting-Yu Lai ◽  
Jerry Cao ◽  
Li-Chung Hsu ◽  
Tsai-Chen Chiang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Survival Data ◽  
Metastatic Potential ◽  
Gene Expression Omnibus ◽  
High Expression ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cancer Tissue ◽  
Pancreatic Cancer Cells

Abstract Background A major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the significant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis. Methods We analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found candidate genes that were differentially expressed in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and verified our finding with the survival data of patients with PDAC from the website of The Human Protein Atlas. Results We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC. Conclusions PSCs stimulated PDAC cells to secrete S100A9, which acts as a chemoattractant to attract circulatory monocytes into cancer microenvironment and induces expression of PD-L1 on macrophages. High expression of S100A9 and PD-L1 was associated with worse overall survival in a cohort of patients with PDAC.

scholarly journals The Isoflavone Puerarin Exerts Anti-Tumor Activitiy in Pancreatic Ductal Adenocarcinoma by Suppressing Akt/mTOR Activity

2021 ◽  
Author(s):  
Hengyue Zhu ◽  
Hong Lu ◽  
Yanyi Xiao ◽  
Hangcheng Guo ◽  
Yangyang Guo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Mtor Signaling ◽  
Ductal Adenocarcinoma ◽  
Flavonoid Compound ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Inhibition Of Proliferation ◽  
Pancreatic Cancer Cells ◽  
Mtor Activity

Abstract Background: Puerarin (7,4’-dihydroxyisoflavone-8-β-glucopyranoside) is a natural flavonoid compound isolated from the traditional Chinese herb Radix puerariae. Recent studies have demonstrated that puerarin has potential anti-tumor effects via induction of apoptosis and inhibition of proliferation. However, the effect and molecular mechanism of puerarin in pancreatic ductal adenocarcinoma (PDAC) remains unknown.Methods: The effects of puerarin on the proliferation, apoptosis, migration and invasion of pancreatic cancer cells (PCCs), and tumor growth and metastasis in PDAC xenograft mouse model were performed. In addition, Akt/mTOR signaling activity was evaluated both in vivo and in vitro.Results: Puerarin treatment significantly repressed PCC proliferation in concentration- and time-dependent manners. Puerarin induced the mitochondrial-dependent apoptosis of PCCs by causing a Bcl-2/Bax imbalance. Moreover, puerarin inhibited PCC migration and invasion by antagonizing epithelial-mesenchymal transition (EMT). In nude mouse model, PDAC growth and metastasis were reduced by puerarin administration. Mechanistically, puerarin exerted its therapeutic effects on PDAC by suppressing Akt/mTOR signaling. Importantly, puerarin bound to the kinase domain of mTOR protein, affecting the activity of the surrounding amino acid residues associated with the binding of the ATP-Mg2+ complex. Further studies showed that the inhibitory effects of puerarin on PCCs were abolished by a mTOR activator MHY1485, indicating a crucial role of mTOR in anti-tumor effects of puerarin in PDAC. As a result, puerarin hindered glucose uptake and metabolism by downregulating the oxygen consumption rate (OCR) and the extracellular acidification rate (ECAR) dependent upon HIF-1α and glucose transporter GLUT1.Conclusion: Puerarin has therapeutic potential for the treatment of PDAC by suppressing Akt/mTOR activity.

scholarly journals The Role of S100A9 in the Interaction Between Pancreatic Ductal Adenocarcinoma Cells and Stromal Cells

2020 ◽  
Author(s):  
Pin-Jui Kung ◽  
Ting-Yu Lai ◽  
Jerry Cao ◽  
Li-Chung Hsu ◽  
Tsai-Chen Chiang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Clinical Outcomes ◽  
High Expression ◽  
Pancreatic Stellate Cells ◽  
Ductal Adenocarcinoma ◽  
Cancer Tissue ◽  
Poor Survival ◽  
Programmed Death Ligand 1 ◽  
Pancreatic Cancer Cells ◽  
Programmed Death

Abstract Background: A major feature of the microenvironment in pancreatic ductal adenocarcinoma (PDAC) is the significant amount of extracellular matrix produced by pancreatic stellate cells (PSCs), which have been reported to enhance the invasiveness of pancreatic cancer cells and negatively impact the prognosis. Methods: We analyzed the data from two publicly available microarray datasets deposited in the Gene Expression Omnibus and found that the expression of S100 calcium binding protein A9 (S100A9) was increased in PDAC cells with metastatic potential and PDAC cells cocultured with PSCs. We studied the interaction between PDAC cells and PSCs in vitro and verified our finding with the survival data of patients with PDAC from the website of The Human Protein Atlas.Results: We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC. Conclusions: We found that PSCs stimulated PDAC cells to secrete S100A9, which attracted circulatory monocytes into cancer tissue and enhanced the expression of programmed death-ligand 1 (PD-L1) on macrophages. When analyzing the correlation of S100A9 and PD-L1 expression with the clinical outcomes of patients with PDAC, we ascertained that high expression of S100A9 and PD-L1 was associated with poor survival in patients with PDAC.

scholarly journals Tumor-derived exosomal long noncoding RNA LINC01133, regulated by Periostin, contributes to pancreatic ductal adenocarcinoma epithelial-mesenchymal transition through the Wnt/β-catenin pathway by silencing AXIN2

Oncogene ◽  
2021 ◽  
Vol 40 (17) ◽  
pp. 3164-3179
Author(s):  
Yang Liu ◽  
Tianchi Tang ◽  
Xiaosheng Yang ◽  
Peng Qin ◽  
Pusen Wang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Noncoding Rna ◽  
Pancreatic Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Noncoding Rnas ◽  
Ductal Adenocarcinoma ◽  
Overall Survival Rate ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies and rapidly progressive diseases. Exosomes and long noncoding RNAs (lncRNAs) are emerging as vital mediators in tumor cells and their microenvironment. However, the detailed roles and mechanisms of exosomal lncRNAs in PDAC progression remain unknown. Here, we aimed to clarify the clinical significance and mechanisms of exosomal lncRNA 01133 (LINC01133) in PDAC. We analyzed the expression of LINC01133 in PDAC and found that exosomal LINC01133 expression was high and positively correlated with higher TNM stage and poor overall survival rate of PDAC patients. Further research demonstrated that Periostin could increase exosome secretion and then enhance LINC01133 expression. In addition, Periostin increased p-EGFR, p-Erk, and c-myc expression, and c-myc could bind to the LINC01133 promoter region. These findings suggested that LINC01133 can be regulated by Periostin via EGFR pathway activity. We also observed that LINC01133 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. We subsequently evaluated the effect of LINC01133 on the Wnt/β-catenin pathway and confirmed that LINC01133 can interact with Enhancer Of Zeste Homolog 2 (EZH2) and then promote H3K27 trimethylation. This can further silence AXIN2 and suppress GSK3 activity, ultimately activating β-catenin. Collectively, these data indicate that exosomal LINC01133 plays an important role in pancreatic tumor progression, and targeting LINC01133 may provide a potential treatment strategy for PDAC.

High expression of ErbB3 binding protein 1 (EBP1) predicts poor prognosis of pancreatic ductal adenocarcinoma (PDAC)

Tumor Biology ◽  
2015 ◽  
Vol 36 (12) ◽  
pp. 9189-9199 ◽  
Author(s):  
Chen Gong ◽  
Yixin Zhang ◽  
Yinji Chen ◽  
Haifeng Zhang ◽  
Xiaorong Liu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Poor Prognosis ◽  
Binding Protein ◽  
High Expression ◽  
Ductal Adenocarcinoma

scholarly journals Role of Oxidative and Nitro-Oxidative Damage in Silver Nanoparticles Cytotoxic Effect against Human Pancreatic Ductal Adenocarcinoma Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-15 ◽  
Author(s):  
Ewelina Barcińska ◽  
Justyna Wierzbicka ◽  
Agata Zauszkiewicz-Pawlak ◽  
Dagmara Jacewicz ◽  
Aleksandra Dabrowska ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Pancreatic Cancer ◽  
Silver Nanoparticles ◽  
Oxidative Damage ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cytotoxic Effect ◽  
Mrna Level ◽  
Ductal Adenocarcinoma ◽  
Adenocarcinoma Cells

Pancreatic ductal adenocarcinoma is one of the most aggressive human malignancies, where the 5-year survival rate is less than 4% worldwide. Successful treatment of pancreatic cancer is a challenge for today’s oncology. Several studies showed that increased levels of oxidative stress may cause cancer cells damage and death. Therefore, we hypothesized that oxidative as well as nitro-oxidative stress is one of the mechanisms inducing pancreatic cancer programmed cell death. We decided to use silver nanoparticles (AgNPs) (2.6 and 18 nm) as a key factor triggering the reactive oxygen species (ROS) and reactive nitrogen species (RNS) in pancreatic ductal adenocarcinoma cells (PANC-1). Previously, we have found that AgNPs induced PANC-1 cells death. Furthermore, it is known that AgNPs may induce an accumulation of ROS and alteration of antioxidant systems in different type of tumors, and they are indicated as promising agents for cancer therapy. Then, the aim of our study was to evaluate the implication of oxidative and nitro-oxidative stress in this cytotoxic effect of AgNPs against PANC-1 cells. We determined AgNP-induced increase of ROS level in PANC-1 cells and pancreatic noncancer cell (hTERT-HPNE) for comparison purposes. We found that the increase was lower in noncancer cells. Reduction of mitochondrial membrane potential and changes in the cell cycle were also observed. Additionally, we determined the increase in RNS level: nitric oxide (NO) and nitric dioxide (NO2) in PANC-1 cells, together with increase in family of nitric oxide synthases (iNOS, eNOS, and nNOS) at protein and mRNA level. Disturbance of antioxidant enzymes: superoxide dismutase (SOD1, SOD2, and SOD3), glutathione peroxidase (GPX-4) and catalase (CAT) were proved at protein and mRNA level. Moreover, we showed cells ultrastructural changes, characteristic for oxidative damage. Summarizing, oxidative and nitro-oxidative stress and mitochondrial disruption are implicated in AgNPs-mediated death in human pancreatic ductal adenocarcinoma cells.

High expression of GRK3 is associated with favorable prognosis in pancreatic ductal adenocarcinoma

2018 ◽  
Vol 214 (2) ◽  
pp. 228-232 ◽  
Author(s):  
Wen-Jing Liu ◽  
Li Zhou ◽  
Zhi-Yong Liang ◽  
Wei-Xun Zhou ◽  
Lei You ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Favorable Prognosis

scholarly journals KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Jing Chen ◽  
Cui-Cui Zhao ◽  
Fei-Ran Chen ◽  
Guo-Wei Feng ◽  
Fei Luo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Disease Free Survival ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion

Background. Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods. We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results. We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed ( P < 0.05 ) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) ( P < 0.05 , respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control ( P < 0.05 , respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion. In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

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