scholarly journals Establishment of Tumor Treating Fields Combined With Mild Hyperthermia as Novel Supporting Therapy for Pancreatic Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Liping Bai ◽  
Tobias Pfeifer ◽  
Wolfgang Gross ◽  
Carolina De La Torre ◽  
Shuyang Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Target Genes ◽  
Expression Profiles ◽  
Duct Cell ◽  
Ductal Adenocarcinoma ◽  
Invasive Approach ◽  
Mild Hyperthermia ◽  
Tumor Treating Fields ◽  
Kaplan Meier ◽  
Online Databases

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with poor prognosis and limited therapeutic options. Alternating electrical fields with low intensity called “Tumor Treating Fields” (TTFields) are a new, non-invasive approach with almost no side effects and phase 3 trials are ongoing in advanced PDAC. We evaluated TTFields in combination with mild hyperthermia. Three established human PDAC cell lines and an immortalized pancreatic duct cell line were treated with TTFields and hyperthermia at 38.5°C, followed by microscopy, assays for MTT, migration, colony and sphere formation, RT-qPCR, FACS, Western blot, microarray and bioinformatics, and in silico analysis using the online databases GSEA, KEGG, Cytoscape-String, and Kaplan-Meier Plotter. Whereas TTFields and hyperthermia alone had weak effects, their combination strongly inhibited the viability of malignant, but not those of nonmalignant cells. Progression features and the cell cycle were impaired, and autophagy was induced. The identified target genes were key players in autophagy, the cell cycle and DNA repair. The expression profiles of part of these target genes were significantly involved in the survival of PDAC patients. In conclusion, the combination of TTFields with mild hyperthermia results in greater efficacy without increased toxicity and could be easily clinically approved as supporting therapy.

scholarly journals Integrated Analyses Identify Immune-Related Signature Associated with Qingyihuaji Formula for Treatment of Pancreatic Ductal Adenocarcinoma Using Network Pharmacology and Weighted Gene Co-Expression Network

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Xiang Qian ◽  
Zhuo Chen ◽  
Sha Sha Chen ◽  
Lu Ming Liu ◽  
Ai Qin Zhang
Keyword(s):  
Expression Profiles ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Ductal Adenocarcinoma ◽  
Network Pharmacology ◽  
Active Ingredients ◽  
Kaplan Meier ◽  
Human Protein Atlas

The study aimed to clarify the potential immune-related targets and mechanisms of Qingyihuaji Formula (QYHJ) against pancreatic cancer (PC) through network pharmacology and weighted gene co-expression network analysis (WGCNA). Active ingredients of herbs in QYHJ were identified by the TCMSP database. Then, the putative targets of active ingredients were predicted with SwissTargetPrediction and the STITCH databases. The expression profiles of GSE32676 were downloaded from the GEO database. WGCNA was used to identify the co-expression modules. Besides, the putative targets, immune-related targets, and the critical module genes were mapped with the specific disease to select the overlapped genes (OGEs). Functional enrichment analysis of putative targets and OGEs was conducted. The overall survival (OS) analysis of OGEs was investigated using the Kaplan-Meier plotter. The relative expression and methylation levels of OGEs were detected in UALCAN, human protein atlas (HPA), Oncomine, DiseaseMeth version 2.0 and, MEXPRESS database, respectively. Gene set enrichment analysis (GSEA) was conducted to elucidate the key pathways of highly-expressed OGEs further. OS analyses found that 12 up-regulated OGEs, including CDK1, PLD1, MET, F2RL1, XDH, NEK2, TOP2A, NQO1, CCND1, PTK6, CTSE, and ERBB2 that could be utilized as potential diagnostic indicators for PC. Further, methylation analyses suggested that the abnormal up-regulation of these OGEs probably resulted from hypomethylation, and GSEA revealed the genes markedly related to cell cycle and proliferation of PC. This study identified CDK1, PLD1, MET, F2RL1, XDH, NEK2, TOP2A, NQO1, CCND1, PTK6, CTSE, and ERBB2 might be used as reliable immune-related biomarkers for prognosis of PC, which may be essential immunotherapies targets of QYHJ.

scholarly journals Apoptosis-associated speck-like protein containing a CARD regulates the growth of pancreatic ductal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mitsuhito Koizumi ◽  
Takao Watanabe ◽  
Junya Masumoto ◽  
Kotaro Sunago ◽  
Yoshiki Imamura ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Adaptor Protein ◽  
Ductal Adenocarcinoma ◽  
Kaplan Meier ◽  
Cell Cycle Modulation ◽  
Interfering Rna ◽  
Kaplan Meier Plotter ◽  
In Vitro Data

AbstractApoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein of inflammasomes and a proapoptotic molecule; however, its roles in signal transduction in pancreatic ductal adenocarcinoma (PDAC) cells remain unknown. Here, we clarified the role and mechanisms of action of ASC in PDAC using clinical evidence and in vitro data. ASC expression in PDAC tissues was analyzed using public tumor datasets and immunohistochemistry results of patients who underwent surgery, and PDAC prognosis was investigated using the Kaplan–Meier Plotter. ASC expression in PDAC cells was downregulated using small-interfering RNA, and gene expression was assessed by RNA sequencing. Review of the Oncomine database and immunostaining of surgically removed tissues revealed elevated ASC expression in PDAC tumors relative to non-tumor tissue, indicating poor prognosis. We observed high ASC expression in multiple PDAC cells, with ASC silencing subsequently inhibiting PDAC cell growth and altering the expression of cell cycle-related genes. Specifically, ASC silencing reduced cyclin D1 levels and stopped the cell cycle at the G1 phase but did not modulate the expression of any apoptosis-related molecules. These results show that ASC inhibited tumor progression via cell cycle modulation in PDAC cells and could be a potential therapeutic target.

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 Coordinative control of G2/M phase of the cell cycle by non-coding RNAs in hepatocellular carcinoma

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5787 ◽  
Author(s):  
Jun Shi ◽  
Guangqiang Ye ◽  
Guoliang Zhao ◽  
Xuedong Wang ◽  
Chunhui Ye ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Target Genes ◽  
Expression Profiles ◽  
M Phase ◽  
Non Coding Rnas ◽  
Regulatory Model ◽  
Microarray Analyses ◽  
The Relationship

Objective To investigate the interaction of non-coding RNAs (ncRNAs) in hepatocellular carcinoma. Methods We compared the ncRNAs and mRNAs expression profiles of hepatocellular carcinoma and adjacent tissue by microarray and RT-PCR. The relationship between different ncRNAs and mRNA was analyzed using bioinformatics tools. A regulatory model of ncRNAs in hepatocellular carcinoma cells was developed. Results A total of 1,704 differentially expressed lncRNAs, 57 miRNAs, and 2,093 mRNAs were identified by microarray analyses. There is a co-expression relationship between two ncRNAs (miRNA-125b-2-3p and lncRNA P26302). Bioinformatics analysis demonstrated cyclin-dependent kinases 1 and CyclinA2 as potential targets of miR-125b-2-3p and Polo-like kinase 1 as potential target of lncRNAP26302. All three gene are important components in the G2/M phase of cell cycle. Subsequently real-time polymerase chain reaction (PCR) studies confirmed these microarray results. Conclusion MiR-125b-2-3p and lncRNAP26302 may affect the G2/M phase of the cell cycle through the regulation of their respective target genes. This study shows a role of ncRNAs in pathogenesis of hepatocellular carcinoma at molecular level, providing a basis for the future investigation aiming at early diagnosis and novel treatment of hepatocellular carcinoma.

scholarly journals An Integrative Data Mining for the Identification and Validation of Oncogenic Biomarkers in Pancreatic Carcinoma

2020 ◽  
Author(s):  
Guihua Jin ◽  
Qingqing Ruan ◽  
Fugen Shangguan ◽  
Linhua Lan
Keyword(s):  
Early Diagnosis ◽  
Western Blot ◽  
Pancreatic Carcinoma ◽  
Target Genes ◽  
Expression Profiles ◽  
Human Tumor ◽  
Differentially Expressed ◽  
Ductal Adenocarcinoma ◽  
Pathway Enrichment Analysis ◽  
Diagnosis And Therapy

Abstract Background: Pancreatic carcinoma (PC) is a severe disease associated with high mortality. Although strategies for cancer therapy made great progress, outcomes of pancreatic ductal adenocarcinoma patients remain extremely poor. Therefore, it is urgent to find novel biomarkers and therapeutic targets to improve outcomes of patients. Methods: To identify general applicable targets for early diagnosis and therapy, we selected related microarray data which including three mRNA microarray datasets GSE62165, GSE15471, GSE32676 and two miRNA datasets GSE24279, GSE32678, and combinative analysis was performed by GEO2R. Functional and pathway enrichment analysis were performed using the DAVID database. MiRTarBase, miRWalk, Diana Tools and TBtools were used to get keys. TCGA database, HPA database and western blot experiments were used to verify diagnostic and prognostic value of key genes.Results: By integrating mRNA and miRNA expression profiles, we identified 114 differentially expressed genes (DEGs) and 114 differentially expressed miRNAs (DEMs), respectively. Furthermore, three overlapping key genes, RUNX2, LAMC2 and FBXO32, were found by compared with DEMs target genes and DEGs. In detail, deregulation of 8 key miRNAs were closely related to poor outcomes and participated in crucial genes regulation which may contribute to build a miRNA biomarker panel for prognosis. Moreover, we confirmed that RUNX2 showed a potential property for distinguishing PC and normal people. We also demonstrated that aberrant over-expression of LAMC2 was associated with poor prognosis of PC patients as well as human tumor status and subtypes. The protein levels of RUNX2 and LAMC2 in PC patients were further verified by IHC from Human Protein Atlas and western blot experiments. Conclusions: In summary, our current study identified that RUNX2 and LAMC2 may be promising targets for early diagnosis and therapy of PC patients.

scholarly journals Construction and Clarification of Dynamic Gene Regulatory Network of Cancer Cell Cycle via Microarray Data

2006 ◽  
Vol 2 ◽  
pp. 117693510600200 ◽  
Author(s):  
Cheng-Wei Li ◽  
Yung-Hsiang Chu ◽  
Bor-Sen Chen
Keyword(s):  
Cell Cycle ◽  
Hela Cell ◽  
Dynamic Model ◽  
Gene Regulatory Network ◽  
Cancer Cell ◽  
Microarray Data ◽  
Regulatory Network ◽  
Target Genes ◽  
Expression Profiles ◽  
Gene Regulatory

Background Cell cycle is an important clue to unravel the mechanism of cancer cells. Recently, expression profiles of cDNA microarray data of Cancer cell cycle are available for the information of dynamic interactions among Cancer cell cycle related genes. Therefore, it is more appealing to construct a dynamic model for gene regulatory network of Cancer cell cycle to gain more insight into the infrastructure of gene regulatory mechanism of cancer cell via microarray data. Results Based on the gene regulatory dynamic model and microarray data, we construct the whole dynamic gene regulatory network of Cancer cell cycle. In this study, we trace back upstream regulatory genes of a target gene to infer the regulatory pathways of the gene network by maximum likelihood estimation method. Finally, based on the dynamic regulatory network, we analyze the regulatory abilities and sensitivities of regulatory genes to clarify their roles in the mechanism of Cancer cell cycle. Conclusions Our study presents a systematically iterative approach to discern and characterize the transcriptional regulatory network in Hela cell cycle from the raw expression profiles. The transcription regulatory network in Hela cell cycle can also be confirmed by some experimental reviews. Based on our study and some literature reviews, we can predict and clarify the E2F target genes in G1/S phase, which are crucial for regulating cell cycle progression and tumorigenesis. From the results of the network construction and literature confirmation, we infer that MCM4, MCM5, CDC6, CDC25A, UNG and E2F2 are E2F target genes in Hela cell cycle.

scholarly journals FOXP4-AS1 is a favourable prognostic-related enhancer RNA in ovarian cancer

2021 ◽  
Author(s):  
Tian Hua ◽  
Yun-jie Tian ◽  
Rui-min Wang ◽  
Cai-fen Zhao ◽  
Yun-hong Kong ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Target Gene ◽  
Target Genes ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Rank Test ◽  
Enhancer Rna ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
Cancer Types

Ovarian cancer (OV) is a main cause of death worldwide in female reproductive system malignancies. Enhancer RNAs (eRNAs) are derived from the transcription of enhancers and has attracted increasing attention in cancers recently. However, the biological functions and clinical significance of eRNAs in OV have not been well described presently. We used an integrated data analysis to identify prognostic-related eRNAs in OV. Tissue-specific enhancer-derived RNAs and their regulating genes were considered as putative eRNA-target pairs using the computational pipeline PreSTIGE. Gene expression profiles and clinical data of OV and 32 other cancer types were obtained from the UCSC Xena platform. Altogether, 71 eRNAs candidates showed significant correlation with overall survival of OV samples (Kaplan-Meier log-rank test, p < 0.05). Among which, 23 ones were determined to be correlated with their potential target genes (Spearman’s r > 0.3, p < 0.001). It was found that among the 23 prognostic-related eRNAs, the expression of FOXP4-AS1 has the highest positive correlation with its predicted target gene FOXP4 (Spearman’s r = 0.61). Moreover, the results were further validated by RT-qPCR analysis in an independent OV cohort. Our results suggested the eRNA FOXP4-AS1 expression index may be a favorable independent prognostic bio-marker candidate in OV.

scholarly journals Integrative Analysis of Gene Expression and miRNAs Reveal Biological Pathways Associated with Bud Paradormancy and Endodormancy in Grapevine

Plants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 669
Author(s):  
Shuchi Smita ◽  
Michael Robben ◽  
Anup Deuja ◽  
Monica Accerbi ◽  
Pamela J. Green ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Transcription Factors ◽  
Target Genes ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Enrichment Analysis ◽  
Integrative Analysis ◽  
Meristem Development ◽  
Mirna Abundance

Transition of grapevine buds from paradormancy to endodormancy is coordinated by changes in gene expression, phytohormones, transcription factors, and other molecular regulators, but the mechanisms involved in transcriptional and post-transcriptional regulation of dormancy stages are not well delineated. To identify potential regulatory targets, an integrative analysis of differential gene expression profiles and their inverse relationships with miRNA abundance was performed in paradormant (long day (LD) 15 h) or endodormant (short day (SD), 13 h) Vitis riparia buds. There were 400 up- and 936 downregulated differentially expressed genes in SD relative to LD budsGene set and gene ontology enrichment analysis indicated that hormone signaling and cell cycling genes were downregulated in SD relative to LD buds. miRNA abundance and inverse expression analyses of miRNA target genes indicated increased abundance of miRNAs that negatively regulate genes involved with cell cycle and meristem development in endodormant buds and miRNAs targeting starch metabolism related genes in paradormant buds. Analysis of interactions between abundant miRNAs and transcription factors identified a network with coinciding regulation of cell cycle and epigenetic regulation related genes in SD buds. This network provides evidence for cross regulation occurring between miRNA and transcription factors both upstream and downstream of MYB3R1.

scholarly journals Genome-wide transcriptome profiling uncovers differential miRNAs and lncRNAs in ovaries of Hu sheep at different developmental stages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Samina Shabbir ◽  
Prerona Boruah ◽  
Lingli Xie ◽  
Muhammad Fakhar-e-Alam Kulyar ◽  
Mohsin Nawaz ◽  
...  
Keyword(s):  
Target Genes ◽  
Expression Profiles ◽  
Ovarian Follicle ◽  
Follicular Development ◽  
Differentially Expressed ◽  
Ovary Development ◽  
Estrogen Metabolism ◽  
Genome Wide ◽  
Micro Rnas ◽  
Hu Sheep

AbstractOvary development is an important determinant of the procreative capacity of female animals. Here, we performed genome-wide sequencing of long non-coding RNAs (lncRNAs) and mRNAs on ovaries of 1, 3 and 8 months old Hu sheep to assess their expression profiles and roles in ovarian development. We identified 37,309 lncRNAs, 45,404 messenger RNAs (mRNAs) and 330 novel micro RNAs (miRNAs) from the transcriptomic analysis. Six thousand, seven hundred and sixteen (6716) mRNAs and 1972 lncRNAs were significantly and differentially expressed in ovaries of 1 month and 3 months old Hu sheep (H1 vs H3). These mRNAs and target genes of lncRNAs were primarily enriched in the TGF-β and PI3K-Akt signalling pathways which are closely associated with ovarian follicular development and steroid hormone biosynthesis regulation. We identified MSTRG.162061.1, MSTRG.222844.7, MSTRG.335777.1, MSTRG.334059.16, MSTRG.188947.6 and MSTRG.24344.3 as vital genes in ovary development by regulating CTNNB1, CCNA2, CDK2, CDC20, CDK1 and EGFR expressions. A total of 2903 mRNAs and 636 lncRNAs were differentially expressed in 3 and 8 months old ovaries of Hu sheep (H3 vs H8); and were predominantly enriched in PI3K-Akt, progesterone-mediated oocyte maturation, estrogen metabolism, ovulation from the ovarian follicle and oogenesis pathways. These lncRNAs were also found to regulate FGF7, PRLR, PTK2, AMH and INHBA expressions during follicular development. Our result indicates the identified genes participate in the development of the final stages of follicles and ovary development in Hu sheep.

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