scholarly journals MicroRNAs Deregulated in Intraductal Papillary Mucinous Neoplasm Converge on Actin Cytoskeleton-Related Pathways That Are Maintained in Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2369
Author(s):  
Elena Fernandez-Castañer ◽  
Maria Vila-Casadesus ◽  
Elena Vila-Navarro ◽  
Carolina Parra ◽  
Juan Jose Lozano ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Structure ◽  
Mrna Translation ◽  
Pancreatic Tissue ◽  
Functional Enrichment ◽  
Ductal Adenocarcinoma ◽  
Mirna Regulation ◽  
Pancreatic Cell ◽  
Potential Implication

Intraductal papillary mucinous neoplasms (IPMN) are pancreatic cystic lesions that can develop into pancreatic ductal adenocarcinoma (PDAC). Although there is an increasing incidence of IPMN diagnosis, the mechanisms of formation and progression into invasive cancer remain unclear. MicroRNAs (miRNAs) are small non-coding RNAs, repressors of mRNA translation, and promising diagnostic biomarkers for IPMN and PDAC. Functional information on the role of early-altered miRNAs in this setting would offer novel strategies for tracking the IPMN-to-PDAC progression. In order to detect mRNAs that are likely to be under miRNA regulation in IPMNs, whole transcriptome and miRNome data from normal pancreatic tissue (n = 3) and IPMN lesions (n = 4) were combined and filtered according to negative correlation and miRNA-target prediction databases by using miRComb R package. Further comparison analysis with PDAC data allowed us to obtain a subset of miRNA-mRNA pairs shared in IPMN and PDAC. Functional enrichment analysis unravelled processes that are mainly related with cell structure, actin cytoskeleton, and metabolism. MiR-181a appeared as a master regulator of these processes. The expression of selected miRNA-mRNA pairs was validated by qRT-PCR in an independent cohort of patients (n = 40), and then analysed in different pancreatic cell lines. Finally, we generated a cellular model of HPDE cells stably overexpressing miR-181a, which showed a significant alteration of actin cytoskeleton structures accompanied by a significant downregulation of EPB41L4B and SEL1L expression. In situ hybridization of miR-181a and immunohistochemistry of EPB41L4B and SEL1L in pancreatic tissues (n = 4 Healthy; n = 3 IPMN; n = 4 PDAC) were also carried out. In this study, we offer insights on the potential implication of miRNA alteration in the regulation of structural and metabolic changes that pancreatic cells experience during IPMN establishment and that are maintained in PDAC.

scholarly journals Organoids from the Human Fetal and Adult Pancreas

2019 ◽  
Vol 19 (12) ◽  
Author(s):  
Jeetindra R. A. Balak ◽  
Juri Juksar ◽  
Françoise Carlotti ◽  
Antonio Lo Nigro ◽  
Eelco J. P. de Koning
Keyword(s):  
Cell Biology ◽  
Cell Formation ◽  
Pancreatic Tissue ◽  
Ductal Adenocarcinoma ◽  
Disease Modelling ◽  
In Vivo Models ◽  
Pancreatic Cell ◽  
Culture Techniques

Abstract Purpose of Review Novel 3D organoid culture techniques have enabled long-term expansion of pancreatic tissue. This review comprehensively summarizes and evaluates the applications of primary tissue–derived pancreatic organoids in regenerative studies, disease modelling, and personalized medicine. Recent Findings Organoids derived from human fetal and adult pancreatic tissue have been used to study pancreas development and repair. Generated adult human pancreatic organoids harbor the capacity for clonal expansion and endocrine cell formation. In addition, organoids have been generated from human pancreatic ductal adenocarcinoma in order to study tumor behavior and assess drug responses. Summary Pancreatic organoids constitute an important translational bridge between in vitro and in vivo models, enhancing our understanding of pancreatic cell biology. Current applications for pancreatic organoid technology include studies on tissue regeneration, disease modelling, and drug screening.

scholarly journals Robo2 Predicts a Better Prognosis and Inhibits Malignant Behavior in Vivo in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Cheng Ding ◽  
Yatong Li ◽  
Shunda Wang ◽  
Cheng Xing ◽  
Lixin Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Western Blot ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Rna Sequencing ◽  
Cell Lines ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Pdac Cell ◽  
Pancreatic Cell

Abstract BackgroundPancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with an extremely poor prognosis and a high mortality rate. Genome-wide studies have shown that the SLIT/ROBO signaling pathway plays an important role in pancreatic tumor development and progression. However, the effect and mechanism of ROBO2 in the progression of pancreatic cancer remains largely unknown.MethodsIn this study, real-time polymerase chain reaction (RT-PCR) and western blot analyses were adopted to evaluate the expression level of ROBO2 and proteins in pancreatic cell lines. Cell migration and invasion and cell proliferation were conducted in AsPC-1 and MIA PaCa-2 cell lines. RNA sequencing and western blot were undertaken to explore the mechanisms and potential targeted molecules. ROBO2 expression in tumor tissues was evaluated by immunohistochemistry in 95 patients.ResultsROBO2 expression was downregulated in PDAC cell lines and tissue samples. A high level of ROBO2 was associated with good overall survival. Upregulation of ROBO2 inhibited PDAC cell proliferation, migration, and invasion, whereas the opposite results were found in the ROBO2 downregulation group. In addition, xenograft animal models further confirmed the effect of ROBO2 on proliferation. Finally, the RNA sequencing results indicated that ROBO2 facilitates anti-tumorigenicity partly via inhibiting ECM1 in PDAC. ConclusionsOur work suggests that ROBO2 inhibits tumor progression in PDAC and may serve as a predictive biomarker and therapeutic target in PDAC.

scholarly journals Transcriptomic Profiling Identifies DCBLD2 as a Diagnostic and Prognostic Biomarker in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Zengyu Feng ◽  
Kexian Li ◽  
Yulian Wu ◽  
Chenghong Peng
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Extracellular Vesicles ◽  
Immune Cell ◽  
Cox Regression ◽  
Univariate Analysis ◽  
Functional Enrichment ◽  
Ductal Adenocarcinoma ◽  
Survival Curves ◽  
Cox Regression Analysis ◽  
Calibration Curves

Background: Accumulating evidence shows that the elevated expression of DCBLD2 (discoidin, CUB and LCCL domain-containing protein 2) is associated with unfavorable prognosis of various cancers. However, the correlation of DCBLD2 expression value with the diagnosis and prognosis of pancreatic ductal adenocarcinoma (PDAC) has not yet been elucidated. Methods: Univariate Cox regression analysis was used to screen robust survival-related genes. Expression pattern of selected genes was investigated in PDAC tissues and normal tissues from multiple cohorts. Kaplan–Meier (K–M) survival curves, ROC curves and calibration curves were employed to assess prognostic performance. The relationship between DCBLD2 expression and immune cell infiltrates was conducted by CIBERSORT software. Biological processes and KEGG pathway enrichment analyses were adopted to clarify the potential function of DCBLD2 in PDAC. Results: Univariate analysis, K–M survival curves and calibration curves indicated that DCBLD2 was a robust prognostic factor for PDAC with cross-cohort compatibility. Upregulation of DCBLD2 was observed in dissected PDAC tissues as well as extracellular vesicles from both plasma and serum samples of PDAC patients. Both DCBLD2 expression in tissue and extracellular vesicles had significant diagnostic value. Besides, DCBLD2 expression was correlated with infiltrating level of CD8+ T cells and macrophage M2 cells. Functional enrichment revealed that DCBLD2 might be involved in cell motility, angiogenesis, and cancer-associated pathways. Conclusion: Our study systematically analyzed the potential diagnostic, prognostic and therapeutic value of DCBLD2 in PDAC. All the findings indicated that DCBLD2 might play a considerably oncogenic role in PDAC with diagnostic, prognostic and therapeutic potential. These preliminary results of bioinformatics analyses need to be further validated in more prospective studies.

Utility of CT Radiomics Features in Differentiation of Pancreatic Ductal Adenocarcinoma From Normal Pancreatic Tissue

2019 ◽  
Vol 213 (2) ◽  
pp. 349-357 ◽  
Author(s):  
Linda C. Chu ◽  
Seyoun Park ◽  
Satomi Kawamoto ◽  
Daniel F. Fouladi ◽  
Shahab Shayesteh ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Pancreatic Tissue ◽  
Ductal Adenocarcinoma ◽  
Normal Pancreatic Tissue

scholarly journals Identification of novel genes associated with a poor prognosis in pancreatic ductal adenocarcinoma via a bioinformatics analysis

2019 ◽  
Vol 39 (8) ◽  
Author(s):  
Jun Zhou ◽  
Xiaoliang Hui ◽  
Ying Mao ◽  
Liya Fan
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Bioinformatics Analysis ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Ductal Adenocarcinoma ◽  
Peroxisome Proliferator ◽  
Integrin Subunit ◽  
Hub Genes ◽  
Potential Biomarker ◽  
Km Plotter

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a class of the commonest malignant carcinomas. The present study aimed to elucidate the potential biomarker and prognostic targets in PDAC. The array data of GSE41368, GSE43795, GSE55643, and GSE41369 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) and differentially expressed microRNAs (DEmiRNAs) in PDAC were obtained by using GEO2R, and overlapped DEGs were acquired with Venn Diagrams. Functional enrichment analysis of overlapped DEGs and DEmiRNAs was conducted with Metascape and FunRich, respectively. The protein–protein interaction (PPI) network of overlapped DEGs was constructed by STRING and visualized with Cytoscape. Overall survival (OS) of DEmiRNAs and hub genes were investigated by Kaplan–Meier (KM) plotter (KM plotter). Transcriptional data and correlation analyses among hub genes were verified through GEPIA and Human Protein Atlas (HPA). Additionally, miRNA targets were searched using miRTarBase, then miRNA–DEG regulatory network was visualized with Cytoscape. A total of 32 DEmiRNAs and 150 overlapped DEGs were identified, and Metascape showed that DEGs were significantly enriched in cellular chemical homeostasis and pathways in cancer, while DEmiRNAs were mainly enriched in signal transduction and Glypican pathway. Moreover, seven hub genes with a high degree, namely, V-myc avian myelocytomatosis viral oncogene homolog (MYC), solute carrier family 2 member 1 (SLC2A1), PKM, plasminogen activator, urokinase (PLAU), peroxisome proliferator activated receptor γ (PPARG), MET proto-oncogene, receptor tyrosine kinase (MET), and integrin subunit α 3 (ITGA3), were identified and found to be up-regulated between PDAC and normal tissues. miR-135b, miR-221, miR-21, miR-27a, miR-199b-5p, miR-143, miR-196a, miR-655, miR-455-3p, miR-744 and hub genes predicted poor OS of PDAC. An integrative bioinformatics analysis identified several hub genes that may serve as potential biomarkers or targets for early diagnosis and precision target treatment of PDAC.

scholarly journals Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors

2016 ◽  
Vol 397 (9) ◽  
pp. 871-881 ◽  
Author(s):  
Anthony J. O’Donoghue ◽  
Sam L. Ivry ◽  
Chaity Chaudhury ◽  
Daniel R. Hostetter ◽  
Douglas Hanahan ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immunoblot Analysis ◽  
Pancreatic Tissue ◽  
Tumor Burden ◽  
Ductal Adenocarcinoma ◽  
Aspartyl Protease ◽  
Altered Expression ◽  
Cathepsin E ◽  
Stage Disease ◽  
End Stage

Abstract The cathepsin family of lysosomal proteases is increasingly being recognized for their altered expression in cancer and role in facilitating tumor progression. The aspartyl protease cathepsin E is overexpressed in several cancers and has been investigated as a biomarker for pancreatic ductal adenocarcinoma (PDAC). Here we show that cathepsin E expression in mouse PDAC tumors is increased by more than 400-fold when compared to healthy pancreatic tissue. Cathepsin E accumulates over the course of disease progression and accounts for more than 3% of the tumor protein in mice with end-stage disease. Through immunoblot analysis we determined that only procathepsin E exists in mouse PDAC tumors and cell lines derived from these tumors. By decreasing the pH, this procathepsion E is converted to the mature form, resulting in an increase in proteolytic activity. Although active site inhibitors can bind procathepsin E, treatment of PDAC mice with the aspartyl protease inhibitor ritonavir did not decrease tumor burden. Lastly, we used multiplex substrate profiling by mass spectrometry to identify two synthetic peptides that are hydrolyzed by procathepsin E near neutral pH. This work represents a comprehensive analysis of procathepsin E in PDAC and could facilitate the development of improved biomarkers for disease detection.

scholarly journals Dysregulation of miRNAs Targeting the IGF-1R Pathway in Pancreatic Ductal Adenocarcinoma

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1856
Author(s):  
Maria Dobre ◽  
Vlad Herlea ◽  
Cătălina Vlăduţ ◽  
Mihai Ciocîrlan ◽  
Vasile Daniel Balaban ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathway ◽  
Treatment Options ◽  
Therapy Resistance ◽  
Pancreatic Disease ◽  
Pancreatic Tissue ◽  
Ductal Adenocarcinoma ◽  
Normal Tissues ◽  
Pdac Tissue

Background: Pancreatic ductal adenocarcinoma (PDAC), the most prevalent neoplastic lethal pancreatic disease, has a poor prognosis and an increasing incidence. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is considered to be a contributing factor to the progression, metastasis, and therapy resistance of PDAC. Currently available treatment options for PDAC are limited, but microRNAs (miRNAs) may represent a new therapeutic strategy for targeting genes involved in the IGF-1R signaling pathway. Method: We investigated the expression levels of 21 miRNAs involved in the IGF-1R signaling pathway in pancreatic tissue from 38 patients with PDAC and 11 controls (five patients with chronic pancreatitis and six patients with normal pancreatic tissue). Results: We found 19 differentially expressed miRNAs between the PDAC cases and the controls. In particular, miR-100-5p, miR-145-5p, miR-29c-3p, miR-9-5p, and miR-195-5p were exclusively downregulated in PDAC tissue but not in chronic pancreatitis or normal pancreatic tissues; both control types presented similar levels. We also identified miR-29a-3p, miR-29b-3p, and miR-7-5p as downregulated miRNAs in PDAC tissues as compared with normal tissues but not with pancreatitis tissues. Conclusions: We identified a panel of miRNAs that could represent putative therapeutic targets for the development of new miRNA-based therapies for PDAC.

Incidentally discovered pancreatic ductal adenocarcinoma: Is detection of asymptomatic cancer associated with better outcomes than symptomatic cancer?

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 243-243
Author(s):  
Yoshinori Takeda ◽  
Akio Saiura ◽  
Yoshihiro Mise ◽  
Takeaki Ishizawa ◽  
Yosuke Inoue ◽  
...  
Keyword(s):  
Early Detection ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Surgical Resection ◽  
Early Stage ◽  
Ductal Adenocarcinoma ◽  
Incomplete Resection ◽  
Long Term Outcomes ◽  
Potential Implication ◽  
Treatment Type

243 Background: The number of incidentally discovered asymptomatic pancreatic ductal adenocarcinoma (APDAC) has been increasing along with recent wide spread use of imaging studies in general practice. However, the clinical implication in early detection of asymptomatic pancreatic cancer remains yet to be determined. In this study, we reviewed our experience of patients with PDAC in high volume cancer center and compared the characteristics and long-term outcomes between those with APDAC and symptomatic PDAC (SPDAC). Methods: This retrospective study included 569 consecutive patients with PDAC initially treated in our institution from January 2007 to December 2012. Median follow-up period was 29 months for the survivors. Two hundred and fifty patients underwent surgical resection and 319 patients were deemed unresectable. The patient’s demographics, tumor locations, pathologic stages, and treatment type received, and the overall survival (OS) were compared between the patients with APDAC and those with SPDAC. Results: One hundred and sixty-three patients (29%) presented without any subjective symptoms. When compared with SPDAC, APDAC was associated with early stage (stage I, 6% vs. 1%, p<0.01). Among 163 patients with APDAC, 104 patients (64%) underwent surgical resection, while only 146 patients (36%) out of 406 SPDAC underwent resection ( p<0.01). The 5-year OS rate of the patients with APDAC was 18%, comparing with 7% for those with SPDAC ( p<0.01). Among the patients who underwent resection, the presence of symptoms did not affect the chance of incomplete resection (R1, 12% vs. 22% for patients with APDAC and SPDAC, respectively, p=0.06) and the 5-year OS rate (23% vs. 22%, p=0.09). However, the patients with SPDAC required complex operation (concomitant vascular resection and reconstruction 56% vs. 29% for those with APDAC, p<0.01). Conclusions: Asymptomatic PDAC is associated with better long-term outcomes than symptomatic PDAC due to early stage at presentation and higher chance of resectability. Our findings highlight the potential implication of screening program for early detection of PDAC for selected high-risk patient population.

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