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A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer.

ABSTRACT: In this study a microRNA (miRNA) signature was identified in a gemcitabine resistant pancreatic ductal adenocarcinoma (PDAC) cell line model (BxPC3-GZR) and this signature was further examined in advanced PDAC tumor specimens from The Cancer Genome Atlas (TCGA) database. BxPC3-GZR showed a mesenchymal phenotype, expressed high levels of CD44 and showed a highly significant deregulation of 17 miRNAs. Based on relevance to cancer, a seven-miRNA signature (miR-100, miR-125b, miR-155, miR-21, miR-205, miR-27b and miR-455-3p) was selected for further studies. A strong correlation was observed for six of the seven miRNAs in 43 advanced tumor specimens compared to normal pancreas tissue. To assess the functional relevance we initially focused on miRNA-125b, which is over-expressed in both the BxPC3-GZR model and advanced PDAC tumor specimens. Knockdown of miRNA-125b in BxPC3-GZR and Panc-1 cells caused a partial reversal of the mesenchymal phenotype and enhanced response to gemcitabine. Moreover, RNA-seq data from each of 40 advanced PDAC tumor specimens from the TCGA data base indicate a negative correlation between expression of miRNA-125b and five of six potential target genes (BAP1, BBC3, NEU1, BCL2, STARD13). Thus far, two of these target genes, BBC3 and NEU1, that are tumor suppressor genes but not yet studied in PDAC, appear to be functional targets of miR-125b since knockdown of miR125b caused their up regulation. These miRNAs and their molecular targets may serve as targets to enhance sensitivity to chemotherapy and reduce metastatic spread.

SUBMITTER: Bera A

PROVIDER: S-EPMC4153643 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer.

Bera Alakesh A VenkataSubbaRao Kolaparthi K Manoharan Muthu Saravanan MS Hill Ping P Freeman James W JW

PloS one 20140903 9

In this study a microRNA (miRNA) signature was identified in a gemcitabine resistant pancreatic ductal adenocarcinoma (PDAC) cell line model (BxPC3-GZR) and this signature was further examined in advanced PDAC tumor specimens from The Cancer Genome Atlas (TCGA) database. BxPC3-GZR showed a mesenchymal phenotype, expressed high levels of CD44 and showed a highly significant deregulation of 17 miRNAs. Based on relevance to cancer, a seven-miRNA signature (miR-100, miR-125b, miR-155, miR-21, miR-20 ...[more]

PMID: 25184537

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Project description:Pancreatic cancer (PC) is known for its high degree of heterogeneity and exceptionally adverse outcome. While disulfidptosis is the most recently identified form of cell death, the predictive and therapeutic value of disulfidptosis-related genes (DRGs) for PC remains unknown. RNA sequencing data with the follow-up information, were retrieved from the TCGA and ICGC databases. Consensus clustering analysis was conducted on patient data using R software. Subsequently, the LASSO regression analysis was conducted to create a prognostic signature for foreseeing the outcome of PC. Differences in relevant pathways, mutational landscape, and tumor immune microenvironment were compared between PC samples with different risk levels. Finally, we experimentally confirmed the impact of DSG3 on the invasion and migration abilities of PC cells. All twenty DRGs were found to be hyperexpressed in PC tissues, and fourteen of them significantly associated with PC survival. Using consensus clustering analysis based on these DRGs, four DRclusters were identified. Additionally, altogether 223 differential genes were evaluated between clusters, indicating potential biological differences between them. Four gene clusters (geneClusters) were recognized according to these genes, and a 10-gene prognostic signature was created. High-risk patients were found to be primarily enriched in signaling pathways related to the cell cycle and p53. Furthermore, the rate of mutations was markedly higher in high-risk patients, besides important variations were present in terms of immune microenvironment and chemotherapy sensitivity among patients with different risk levels. DSG3 could appreciably enhance the invasion and migration of PC cells. This work, based on disulfidoptosis-related genes (DRGs), holds the promise of classifying PC patients and predicting their prognosis, mutational landscape, immune microenvironment, and drug therapy. These insights could boost an improvement in a better comprehension of the role of DRGs in PC as well as provide new opportunities for prognostic prediction and more effective treatment strategies.

Dataset Information

A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer.

Publications

A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer.

Similar Datasets

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