scholarly journals A Network-Based Approach for Identification of Subtype-Specific Master Regulators in Pancreatic Ductal Adenocarcinoma

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 155
Author(s):  
Yuchen Zhang ◽  
Lina Zhu ◽  
Xin Wang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Network Inference ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Regulatory Mechanism ◽  
Expression Profiles ◽  
Strong Association ◽  
Predictive Biomarkers ◽  
Integrative Analysis ◽  
Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), the predominant subtype of pancreatic cancer, has been reported with equal mortality and incidence for decades. The lethality of PDAC is largely due to its late presentation, when surgical resection is no longer an option. Similar to other major malignancies, it is now clear that PDAC is not a single disease, posing a great challenge to precise selection of patients for optimized adjuvant therapy. A representative study found that PDAC comprises four distinct molecular subtypes: squamous, pancreatic progenitor, immunogenic, and aberrantly differentiated endocrine exocrine (ADEX). However, little is known about the molecular mechanisms underlying specific PDAC subtypes, hampering the design of novel targeted agents. In this study we performed network inference that integrates miRNA expression and gene expression profiles to dissect the miRNA regulatory mechanism specific to the most aggressive squamous subtype of PDAC. Master regulatory analysis revealed that the particular subtype of PDAC is predominantly influenced by miR-29c and miR-192. Further integrative analysis found miR-29c target genes LOXL2, ADAM12 and SERPINH1, which all showed strong association with prognosis. Furthermore, we have preliminarily revealed that the PDAC cell lines with high expression of these miRNA target genes showed significantly lower sensitivities to multiple anti-tumor drugs. Together, our integrative analysis elucidated the squamous subtype-specific regulatory mechanism, and identified master regulatory miRNAs and their downstream genes, which are potential prognostic and predictive biomarkers.

scholarly journals HSP90 Inhibition Synergizes with Cisplatin to Eliminate Basal-like Pancreatic Ductal Adenocarcinoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6163
Author(s):  
Katharina M. Ewers ◽  
Shilpa Patil ◽  
Waltraut Kopp ◽  
Jürgen Thomale ◽  
Tabea Quilitz ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Predictive Biomarkers ◽  
Hsp90 Inhibitor ◽  
Ductal Adenocarcinoma ◽  
Ovarian Cancer Cells ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Platinum Sensitive

To improve the treatment of pancreatic ductal adenocarcinoma (PDAC), a promising strategy consists of personalized chemotherapy based on gene expression profiles. Investigating a panel of PDAC-derived human cell lines, we found that their sensitivities towards cisplatin fall in two distinct classes. The platinum-sensitive class is characterized by the expression of GATA6, miRNA-200a, and miRNA-200b, which might be developable as predictive biomarkers. In the case of resistant PDAC cells, we identified a synergism of cisplatin with HSP90 inhibitors. Mechanistic explanations of this synergy include the degradation of Fanconi anemia pathway factors upon HSP90 inhibition. Treatment with the drug combination resulted in increased DNA damage and chromosome fragmentation, as we have reported previously for ovarian cancer cells. On top of this, HSP90 inhibition also enhanced the accumulation of DNA-bound platinum. We next investigated an orthotopic syngeneic animal model consisting of tumors arising from KPC cells (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre, C57/BL6 genetic background). Here again, when treating established tumors, the combination of cisplatin with the HSP90 inhibitor onalespib was highly effective and almost completely prevented further tumor growth. We propose that the combination of platinum drugs and HSP90 inhibitors might be worth testing in the clinics for the treatment of cisplatin-resistant PDACs.

scholarly journals The MYEOV-MYC association promotes oncogenic miR-17/93-5p expression in pancreatic ductal adenocarcinoma

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Hongzhang Shen ◽  
Fuqiang Ye ◽  
Dongchao Xu ◽  
Liangliang Fang ◽  
Xiaofeng Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Ductal Adenocarcinoma ◽  
Invasion And Migration ◽  
And Migration

AbstractPancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy worldwide. As metastasis and malignant progression are primarily responsible for the poor clinical outcomes of PDAC, identifying key genes involved in these processes and the underlying molecular mechanisms of PDAC is vital. In this study, by analyzing TCGA PDAC data and matched GTEx data, we found that MYEOV expression is associated with poor survival in PDAC patients and higher in carcinoma tissues than in healthy tissues. Elevated levels of MYEOV led to enhanced cell proliferation, invasion and migration in vitro and in vivo. Transcriptome analysis results revealed that MYEOV mediates global alterations in gene expression profiles in PDAC cells. MiRNA-seq analysis showed that MYEOV regulates the expression levels of miR-17-5p and miR-93-5p, and its depletion resulted in reduced cell proliferation, invasion and migration, as observed in MYEOV-knockdown PDAC cells. These effects are likely due to the ability of MYEOV to regulate enrichment of the transcription factor MYC at the gene promoter regions of the two miRNAs. Furthermore, we identified a complex containing MYEOV and MYC in the nucleus, providing additional evidence for the association of MYEOV with MYC. Taken together, our results suggest that MYEOV promotes oncogenic miR-17/93-5p expression by associating with MYC, contributing to PDAC progression.

scholarly journals Discovering key transcriptomic regulators in pancreatic ductal adenocarcinoma using Dirichlet process Gaussian mixture model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sk Md Mosaddek Hossain ◽  
Aanzil Akram Halsana ◽  
Lutfunnesa Khatun ◽  
Sumanta Ray ◽  
Anirban Mukhopadhyay
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Mixture Model ◽  
Cancer Progression ◽  
Dirichlet Process ◽  
Network Inference ◽  
Correlation Method ◽  
Gaussian Mixture ◽  
Ductal Adenocarcinoma ◽  
Gene Regulatory Network Inference ◽  
Gene Modules

AbstractPancreatic Ductal Adenocarcinoma (PDAC) is the most lethal type of pancreatic cancer, late detection leading to its therapeutic failure. This study aims to determine the key regulatory genes and their impacts on the disease’s progression, helping the disease’s etiology, which is still mostly unknown. We leverage the landmark advantages of time-series gene expression data of this disease and thereby identified the key regulators that capture the characteristics of gene activity patterns in the cancer progression. We have identified the key gene modules and predicted the functions of top genes from a reconstructed gene association network (GAN). A variation of the partial correlation method is utilized to analyze the GAN, followed by a gene function prediction task. Moreover, we have identified regulators for each target gene by gene regulatory network inference using the dynamical GENIE3 (dynGENIE3) algorithm. The Dirichlet process Gaussian process mixture model and cubic spline regression model (splineTimeR) are employed to identify the key gene modules and differentially expressed genes, respectively. Our analysis demonstrates a panel of key regulators and gene modules that are crucial for PDAC disease progression.

scholarly journals Genome-wide miRNA profiling of villus and decidua of recurrent spontaneous abortion patients

Reproduction ◽  
2014 ◽  
Vol 148 (1) ◽  
pp. 33-41 ◽  
Author(s):  
Fulu Dong ◽  
Yuan Zhang ◽  
Fei Xia ◽  
Yi Yang ◽  
Sidong Xiong ◽  
...  
Keyword(s):  
Spontaneous Abortion ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Expression Profiles ◽  
Normal Pregnancy ◽  
Recurrent Spontaneous Abortion ◽  
Future Research ◽  
Rna Molecules ◽  
Non Coding Rna ◽  
Transcriptional Gene Regulation

MicroRNAs (miRNAs) are non-coding RNA molecules of about 22 nucleotides that involved in post-transcriptional gene regulation. Evidence indicates that miRNAs play essential roles in endometriosis, pre-eclampsia, infertility and other reproductive system diseases. However, whether miRNAs are involved in recurrent spontaneous abortion (RSA) is unclear. In this work, we analysed the miRNA expression profiles in six pairs of villus or decidua from RSA patients and normal pregnancy (NP) women using a human miRNA microarray. Some of the chip results were confirmed by RT-qPCR. In the villi of RSA patients, expression of hsa-miR-184, hsa-miR-187 and hsa-miR-125b-2 was significantly higher, while expression of hsa-miR-520f, hsa-miR-3175 and hsa-miR-4672 was significantly lower, comparing with those of NP control. As well, a total of five miRNAs (hsa-miR-517c, hsa-miR-519a-1, hsa-miR-522, hsa-miR-520h and hsa-miR-184) were upregulated in the decidua of RSA patients. The target genes of these differentially expressed miRNAs were predicted by miRWalk, and we speculate a network of miRNA regulating RSA by target genes function on adhesion, apoptosis and angiogenesis. Our study may help clarify the molecular mechanisms which are involved in the progression of RSA, and provide a reference for future research.

scholarly journals miR-124 Suppresses Pancreatic Ductal Adenocarcinoma Growth by Regulating Monocarboxylate Transporter 1-Mediated Cancer Lactate Metabolism

2018 ◽  
Vol 50 (3) ◽  
pp. 924-935 ◽  
Author(s):  
De-Hai Wu ◽  
Hao Liang ◽  
Shou-Nan Lu ◽  
Hao Wang ◽  
Zhi-Lei Su ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Intracellular Ph ◽  
Molecular Mechanisms ◽  
Monocarboxylate Transporter ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Lactate Metabolism ◽  
Rt Pcr ◽  
Monocarboxylate Transporter 1

Background/Aims: Increasing evidence shows that reprogramming of energy metabolism is a hallmark of cancer. Considering the emergence of microRNAs as crucial modulators of cancer, this study aimed to better understand the molecular mechanisms of miR-124 in regulating glycolysis in human pancreatic cancer. Methods: RT-PCR was used to investigate the expression of monocarboxylate transporters (MCTs) in pancreatic ductal adenocarcinoma (PDAC) patient samples and the PANC-1 cell line. A public database and immunochemistry were used for comprehensive analysis of MCT1 expression. The targeting of MCT1 by miR-124 was predicted by software and validated for the MCT1 3’-UTR by dual-luciferase reporter analysis. Cell proliferation, apoptosis, migration, xenografting, and the intracellular pH and L-lactate levels were assessed. Hypoxia-inducible factor-α (HIF-1α) and lactate dehydrogenase A (LDH-A) expression levels were determined by RT-PCR and western blotting. Results: MCT1 expression was higher in PDAC tissue than in normal tissue. Inhibition of MCT1 affected lactate metabolism, resulting in a higher intracellular pH and less proliferation of PANC-1 cells. MCT1 was the target gene of miR-124. In in vitro experiments, miR-124 inhibited the glycolytic activity of PANC-1 cells by targeting MCT1, further decreasing the tumor phenotype by increasing the intracellular pH through LDH-A and HIF-1α. In in vivo experiments, overexpression of miR-124 and silencing of MCT1 significantly inhibited tumor growth. Conclusion: miR-124 inhibits the progression of PANC-1 by targeting MCT1 in the lactate metabolic pathway. Our findings provide novel evidence for further functional studies of miR-124, which might be useful for future therapeutic approaches to PDAC.

scholarly journals Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1869 ◽  
Author(s):  
Can Huang ◽  
Wenjun Lan ◽  
Nicolas Fraunhoffer ◽  
Analía Meilerman ◽  
Juan Iovanna ◽  
...  
Keyword(s):  
Cell Death ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Proteasome Inhibitors ◽  
Ductal Adenocarcinoma ◽  
Mitochondrial Stress ◽  
Anticancer Mechanism ◽  
Chemotherapeutic Treatment ◽  
Approved Drugs ◽  
Protein Response

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with almost no curative chemotherapeutic treatment. Besides the development of new compounds, repurposing of approved drugs to treat cancer, alone or in combination, has become an attractive strategy, showing many therapeutic and economic advantages. However, it is necessary to improve our knowledge about the mechanism of cell death elicited by approved drugs itself, but also to rationally develop more powerful multidrug treatments. In this work, we focus our attention on determining the mechanism promoting cell death following trifluoperazine (TFP) treatment, which is an antipsychotic drug with strong anticancer activity in PDAC. We demonstrate that TFP induces cell death by apoptosis and necroptosis, which can be partially inhibited by Z-VAD-FMK as well as necrostatin-1, respectively. This cell death promotion is triggered by a poor ATP content, observed in TFP-treated cells as a consequence of a dramatic decrease in OXPHOS metabolism due to mitochondrial stress. Remarkably, mitochondrial homeostasis was seriously affected, and a loss of mitochondrial membrane potential and ROS overproduction was observed. Moreover, this mitochondrial stress was coupled with an ER stress and the activation of the endoplasmic-reticulum-associated protein degradation (ERAD) and the unf olded protein response (UPR) pathways. We took advantage of this information and inhibited this process by using the proteasome inhibitors MG-132 or bortezomib compounds in combination with TFP and found a significant improvement of the anticancer effect of the TFP on primary PDAC-derived cells. In conclusion, this study not only uncovers the molecular mechanisms that are triggered upon TFP-treatment but also its possible combination with bortezomib for the future development of therapies for pancreatic cancer.

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