scholarly journals Role of miR-30a-3p Regulation of Oncogenic Targets in Pancreatic Ductal Adenocarcinoma Pathogenesis

2020 ◽  
Vol 21 (18) ◽  
pp. 6459
Author(s):  
Hiroki Shimomura ◽  
Reona Okada ◽  
Takako Tanaka ◽  
Yuto Hozaka ◽  
Masumi Wada ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ectopic Expression ◽  
In Silico Analysis ◽  
Molecular Pathogenesis ◽  
Ductal Adenocarcinoma ◽  
Binding Partner ◽  
Passenger Strand ◽  
Silico Analysis ◽  
Mirna Expression Signature

Our recent studies have implicated some passenger strands of miRNAs in the molecular pathogenesis of human cancers. Analysis of the microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) has shown that levels of miR-30a-3p, the passenger strand derived from pre-mir-30a, are significantly downregulated in PDAC tissues. This study aimed to identify the oncogenes closely involved in PDAC molecular pathogenesis under the regulation of miR-30a-3p. Ectopic expression assays showed that miR-30a-3p expression inhibited the aggressiveness of the PDAC cells, suggesting that miR-30a-3p acts as a tumor-suppressive miRNA in PDAC cells. We further identified 102 putative targets of miR-30a-3p regulation in PDAC cells by combining in silico analysis with gene expression data. Of these, ten genes (EPS8, HMGA2, ENDOD1, SLC39A10, TGM2, MGLL, SERPINE1, ITGA2, DTL, and UACA) were independent prognostic factors in multivariate analysis of survival of patients with PDAC (p < 0.01). We also investigated the oncogenic function of the integrin ITGA2 in PDAC cell lines. The integrin family comprises cell adhesion molecules expressed as heterodimeric, transmembrane proteins on the surface of various cells. Overexpression of ITGA2/ITGB1 (an ITGA2 binding partner) was detected in the PDAC clinical specimens. The knockdown of ITGA2 expression attenuated the malignant phenotypes of the PDAC cells. Together, results from these microRNA-based approaches can accelerate our understanding of PDAC molecular pathogenesis.

scholarly journals Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2731
Author(s):  
Takako Tanaka ◽  
Reona Okada ◽  
Yuto Hozaka ◽  
Masumi Wada ◽  
Shogo Moriya ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Topoisomerase Ii ◽  
Survival Rates ◽  
Ectopic Expression ◽  
Molecular Pathogenesis ◽  
Ductal Adenocarcinoma ◽  
Mirna Signature ◽  
Topoisomerase Ii Alpha ◽  
Passenger Strand ◽  
One Year

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, and its prognosis is abysmal; only 25% of patients survive one year, and 5% live for five years. MicroRNA (miRNA) signature analysis of PDAC revealed that both strands of pre-miR-30c (miR-30c-5p, guide strand; miR-30c-2-3p, passenger strand) were significantly downregulated, suggesting they function as tumor-suppressors in PDAC cells. Ectopic expression assays demonstrated that these miRNAs attenuated the aggressiveness of PDAC cells, e.g., cell proliferation, migration, and invasiveness. Through a combination of in silico analyses and gene expression data, we identified 216 genes as putative oncogenic targets of miR-30c-5p and miR-30c-2-3p regulation in PDAC cells. Among these, the expression of 18 genes significantly predicted the 5-year survival rates of PDAC patients (p < 0.01). Importantly, the expression levels of 10 genes (YWHAZ, F3, TMOD3, NFE2L3, ENDOD1, ITGA3, RRAS, PRSS23, TOP2A, and LRRFIP1) were found to be independent prognostic factors for patient survival (p < 0.01). We focused on TOP2A (DNA Topoisomerase II Alpha) and investigated its potential as a therapeutic target for PDAC. The overexpression of TOP2A and its transcriptional activators (SP1 and HMGB2) was detected in PDAC clinical specimens. Moreover, the knockdown of TOP2A enhanced the sensitivity of PDAC cells to anticancer drugs. Our analyses of the PDAC miRNA signature and tumor-suppressive miRNAs provide important insights into the molecular pathogenesis of PDAC.

In silico analysis of the transportome in human pancreatic ductal adenocarcinoma

2016 ◽  
Vol 45 (7) ◽  
pp. 749-763 ◽  
Author(s):  
A. Zaccagnino ◽  
C. Pilarsky ◽  
D. Tawfik ◽  
S. Sebens ◽  
A. Trauzold ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
In Silico ◽  
In Silico Analysis ◽  
Ductal Adenocarcinoma ◽  
Silico Analysis

scholarly journals Molecular pathogenesis of pancreatic ductal adenocarcinoma: Impact of passenger strand of pre-miR-148aon gene regulation

2018 ◽  
Vol 109 (6) ◽  
pp. 2013-2026 ◽  
Author(s):  
Tetsuya Idichi ◽  
Naohiko Seki ◽  
Hiroshi Kurahara ◽  
Haruhi Fukuhisa ◽  
Hiroko Toda ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Pathogenesis ◽  
Ductal Adenocarcinoma ◽  
Passenger Strand

scholarly journals Histone demethylase JMJD3 disrupts spectrin-dependent cytoskeleton in Pancreatic Ductal Adenocarcinoma cells by regulating H exokinase domain containing 1 expression

2020 ◽  
Author(s):  
Zhangang Xiao ◽  
Jing Shen ◽  
Qijie Zhao ◽  
Shixin Xiang ◽  
Yinxin Zhu ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ectopic Expression ◽  
Histone Demethylase ◽  
Ductal Adenocarcinoma ◽  
Histone 3 ◽  
Adenocarcinoma Cells ◽  
Cytoskeleton Disruption ◽  
Demethylation Activity

Abstract Background: JMJD3 is a jmjd domain containing histone demethylase which can remove methyl groups from lysine 27 of histone 3 (H3K27) to active histone methylated genes. Previous studies have demonstrated that JMJD3 played a crucial role in inflammation. Methods: Our study showed that JMJD3 was significantly down-regulated in pancreatic ductal adenocarcinoma (PDAC) cell lines and tissues. Restored expression of JMJD3 inhibited oncogenic phenotypes of PDAC cells, including cell proliferation, cell migration, and in vivo tumorigenicity, indicating a tumor suppressive role. Gene-expression microarray revealed that Hexokinase domain containing 1 (HKDC1) was one of the JMJD3 downstream targets. Results: The expression of JMJD3 and HKDC1 in PDAC tissues was positively correlated. High H3K27 tri-methylation (H3K27me3) status in HKDC1 gene was attenuated by ectopic expression of JMJD3 in PDAC cells, suggested that JMJD3 regulated HKDC1 expression by histone demethylation activity. The tumor suppressive role of HKDC1 in PDAC was also proved. Moreover, HKDC1 was demonstrated to competitively bind to spectrin beta Ⅱ to induce cytoskeleton disruption, which may contribute to tumor suppression. Conclusion: Taken together, our study indicates that JMJD3 may disrupt spectrin-dependent cytoskeleton via activation of HKDC1 to suppress PDAC.

scholarly journals Gene Regulation by Antitumor miR-204-5p in Pancreatic Ductal Adenocarcinoma: The Clinical Significance of Direct RACGAP1 Regulation

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 327 ◽  
Author(s):  
Muhammad Khalid ◽  
Tetsuya Idichi ◽  
Naohiko Seki ◽  
Masumi Wada ◽  
Yasutaka Yamada ◽  
...  
Keyword(s):  
Survival Rate ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Target Genes ◽  
Ectopic Expression ◽  
Disease Free Survival ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion ◽  
Guanosine Triphosphatase ◽  
Disease Free Survival Rate ◽  
Mirna Expression Signature

Previously, we established a microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) tissues using RNA sequencing and found significantly reduced expression of miR-204-5p. Here, we aimed to investigate the functional significance of miR-204-5p and to identify miR-204-5p target genes involved in PDAC pathogenesis. Cancer cell migration and invasion were significantly inhibited by ectopic expression of miR-204-5p in PDAC cells. Comprehensive gene expression analyses and in silico database searches revealed 25 putative targets regulated by miR-204-5p in PDAC cells. Among these target genes, high expression levels of RACGAP1, DHRS9, AP1S3, FOXC1, PRP11, RHBDL2 and MUC4 were significant predictors of a poor prognosis of patients with PDAC. In this study, we focused on RACGAP1 (Rac guanosine triphosphatase-activating protein 1) because its expression was most significantly predictive of PDAC pathogenesis (overall survival rate: p = 0.0000548; disease-free survival rate: p = 0.0014). Overexpression of RACGAP1 was detected in PDAC clinical specimens, and its expression enhanced the migration and invasion of PDAC cells. Moreover, downstream genes affected by RACGAP1 (e.g., MMP28, CEP55, CDK1, ANLN and S100A14) are involved in PDAC pathogenesis. Our strategy to identify antitumor miRNAs and their target genes will help elucidate the molecular pathogenesis of PDAC.

scholarly journals A Proteomic Study on the Personalized Protein Corona of Liposomes. Relevance for Early Diagnosis of Pancreatic DUCTAL Adenocarcinoma and Biomarker Detection

2021 ◽  
Vol 2 (2) ◽  
pp. 82-93
Author(s):  
Luca Digiacomo ◽  
Francesca Giulimondi ◽  
Daniela Pozzi ◽  
Alessandro Coppola ◽  
Vincenzo La Vaccara ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Early Diagnosis ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Protein Corona ◽  
Detection Sensitivity ◽  
Ductal Adenocarcinoma ◽  
Protein Biomarkers ◽  
Ca 19.9 ◽  
Proteomic Study

Due to late diagnosis, high incidence of metastasis, and poor survival rate, pancreatic cancer is one of the most leading cause of cancer-related death. Although manifold recent efforts have been done to achieve an early diagnosis of pancreatic cancer, CA-19.9 is currently the unique biomarker that is adopted for the detection, despite its limits in terms of sensitivity and specificity. To identify potential protein biomarkers for pancreatic ductal adenocarcinoma (PDAC), we used three model liposomes as nanoplatforms that accumulate proteins from human plasma and studied the composition of this biomolecular layer, which is known as protein corona. Indeed, plasma proteins adsorb on nanoparticle surface according to their abundance and affinity to the employed nanomaterial, thus even small differences between healthy and PDAC protein expression levels can be, in principle, detected. By mass spectrometry experiments, we quantified such differences and identified possible biomarkers for PDAC. Some of them are already known to exhibit different expressions in PDAC proteomes, whereas the role of other relevant proteins is still not clear. Therefore, we predict that the employment of nanomaterials and their protein corona may represent a useful tool to amplify the detection sensitivity of cancer biomarkers, which may be used for the early diagnosis of PDAC, with clinical implication for the subsequent therapy in the context of personalized medicine.

scholarly journals Intracellular Na+ Modulates Pacemaking Activity in Murine Sinoatrial Node Myocytes: An In Silico Analysis

2021 ◽  
Vol 22 (11) ◽  
pp. 5645
Author(s):  
Stefano Morotti ◽  
Haibo Ni ◽  
Colin H. Peters ◽  
Christian Rickert ◽  
Ameneh Asgari-Targhi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Membrane Potential ◽  
In Silico ◽  
Sinoatrial Node ◽  
In Silico Analysis ◽  
Ankyrin B ◽  
Deficient Mice ◽  
Silico Analysis ◽  
Bursting Activity

Background: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart’s primary pacemaker, are incompletely understood. Electrical and Ca2+-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na+]i is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na+ homeostasis in SAN pacemaking and test whether [Na+]i dysregulation may contribute to SAN dysfunction. Methods: We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na+ entry (Na+/Ca2+ exchanger, NCX) and removal (Na+/K+ ATPase, NKA). Results: We found that changes in intracellular Na+ homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX- and ankyrin-B-deficient mice due to altered feedback between the Ca2+ and membrane potential clocks underlying SAN firing. Conclusions: Our study generates new testable predictions and insight linking Na+ homeostasis to Ca2+ handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.

scholarly journals Syndecans and Pancreatic Ductal Adenocarcinoma

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 349
Author(s):  
Nausika Betriu ◽  
Juan Bertran-Mas ◽  
Anna Andreeva ◽  
Carlos E. Semino
Keyword(s):  
Extracellular Matrix ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Types ◽  
Ductal Adenocarcinoma ◽  
Physiological Processes ◽  
Extracellular Matrix Components ◽  
Detection And Diagnosis ◽  
And Migration ◽  
Early Detection And Diagnosis

Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.

Sign in / Sign up

Export Citation Format

Share Document