Role of miRNA and cancer stem cells in chemoresistance and pancreatic cancer treatment

Danquah, Michael; Singh, Saurabh; Behrman, Stephen W.; Mahato, Ram I.

doi:10.1517/17425247.2012.722079

Cited by 12 publications

(9 citation statements)

References 16 publications

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“…Studies also showed a role for miRNAs in development of drug resistance in a variety of malignancies [11]. The expression level of miRNA was compared in BxPC3 and BxPC3-GZR cells by μParaflo microfluidic chip miRNA profiling.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, cancer cells with an EMT phenotype and that were resistant to gemcitabine showed down regulation of let-7 members [5], [15], [16]. In vitro studies of PDAC indicate a linkage among EMT, invasiveness and resistance to chemotherapy and other studies support the notion that miRNAs play a role in these processes by regulating gene expression [3], [11].…”

Section: Introductionmentioning

confidence: 88%

“…Recent findings indicate an interrelationship between miRNAs, EMT phenotype, CSCs and chemoresistance [10], [11]. Studies also suggest that miRNAs play a role in regulating the EMT process [3], [11].…”

Section: Introductionmentioning

confidence: 99%

“…Studies also suggest that miRNAs play a role in regulating the EMT process [3], [11]. For instance, miRNAs have been shown to drive EMT by regulating cadherin 1 and additional EMT related molecules [12].…”

Section: Introductionmentioning

confidence: 99%

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A miRNA Signature of Chemoresistant Mesenchymal Phenotype Identifies Novel Molecular Targets Associated with Advanced Pancreatic Cancer

et al. 2014

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A miRNA Signature of Chemoresistant Mesenchymal Phenotype Identifies Novel Molecular Targets Associated with Advanced Pancreatic Cancer

et al. 2014

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“…Recent studies have uncovered novel epigenetic mechanisms such as methylation of lysine in histones to preferentially amplify pro-tumorigenic signaling of cancer cells to EMT (16–19). In particular, a striking correlation between TGF-β1 and EZH2, a histone methyl transferase enzyme in the Polycomb Repressive Complex 2 (PRC2) involved in silencing of genes via H3K27Me, was recognized to regulate EMT (20, 21).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p

Mody

Hung

Alsaggar

et al. 2016

Molecular Cancer Research

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Identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacological inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their anti-tumorigenic effects. Here, 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, significantly reprograms noncoding miRNA (miR) expression and dampens TGFβ1-induced epithelial-to-mesenchymal (EMT) signals in pancreatic cancer. In particular, miR-663a and miR-4787-5p were identified as PDAC-downregulated miRs that were reactivated by DZNep to directly target TGFβ1 for RNA interference. Lentiviral overexpression of miR-663a and miR-4787-5p reduced TGFβ1 synthesis and secretion in PDAC cells and partially phenocopied DZNep’s EMT-resisting effects, whereas locked nucleic acid (LNA) antagomiRs counteracted them. DZNep, miR-663a, and miR-4787-5p reduced tumor burden in vivo and metastases in an orthotopic mouse pancreatic tumor model. Taken together, these findings suggest the epigenetic reprogramming of miRs by synthetic histone methylation reversal agents as a viable approach to attenuate TGFβ1-induced EMT features in human PDAC and uncover putative miR targets involved in the process.

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MicroRNAs in tumor stem cells

Yang

et al. 2015

Oncology and Translational Medicine

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MicroRNAs (miRNAs) are a class of non-coding RNAs that are believed to have a significant role in tumorigenesis and cancer metastasis. Cancer stem cells play a major role in tumor recurrence, metastasis, and drug resistance. Research has shown that miRNAs can promote or inhibit the stemness of cancer stem cells and regulate the differentiation and self-renewal of cancer stem cells. In this article, the phenotype and regulatory mechanisms of miRNAs in cancer stem cells will be described, together with an explanation of their potential role in tumor diagnosis and treatment.

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Role of miRNA and cancer stem cells in chemoresistance and pancreatic cancer treatment

Cited by 12 publications

References 16 publications

A miRNA Signature of Chemoresistant Mesenchymal Phenotype Identifies Novel Molecular Targets Associated with Advanced Pancreatic Cancer

A miRNA Signature of Chemoresistant Mesenchymal Phenotype Identifies Novel Molecular Targets Associated with Advanced Pancreatic Cancer

Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p

MicroRNAs in tumor stem cells

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