Dataset Information

Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p.

ABSTRACT: KRas is mutated in a significant number of human cancers and so there is an urgent therapeutic need to target KRas signalling. To target KRas in lung cancers we used a systems approach of integrating a genome-wide miRNA screen with patient-derived phospho-proteomic signatures of the KRas downstream pathway, and identified miR-193a-3p, which directly targets KRas. Unique aspects of miR-193a-3p biology include two functionally independent target sites in the KRas 3'UTR and clinically significant correlation between miR-193a-3p and KRas expression in patients. Rescue experiments with mutated KRas 3'UTR showed very significantly that the anti-tumour effect of miR-193a-3p is via specific direct targeting of KRas and not due to other targets. Ex vivo and in vivo studies utilizing nanoliposome packaged miR-193a-3p demonstrated significant inhibition of tumour growth, circulating tumour cell viability and decreased metastasis. These studies show the broader applicability of using miR-193a-3p as a therapeutic agent to target KRas-mutant cancer.

SUBMITTER: Seviour EG

PROVIDER: S-EPMC5344721 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p.

Seviour E G EG Sehgal V V Mishra D D Rupaimoole R R Rodriguez-Aguayo C C Lopez-Berestein G G Lee J-S JS Sood A K AK Kim M P MP Mills G B GB Ram P T PT

Oncogene 20160926 10

KRas is mutated in a significant number of human cancers and so there is an urgent therapeutic need to target KRas signalling. To target KRas in lung cancers we used a systems approach of integrating a genome-wide miRNA screen with patient-derived phospho-proteomic signatures of the KRas downstream pathway, and identified miR-193a-3p, which directly targets KRas. Unique aspects of miR-193a-3p biology include two functionally independent target sites in the KRas 3'UTR and clinically significant c ...[more]

PMID: 27669434

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Project description:BackgroundMetastasis is the main cause of death in colorectal cancer (CRC). Circulating tumour cells (CTCs) are regarded as the precursor cells of metastasis. The CTCs, which underwent epithelial-mesenchymal transition (EMT), are associated with metastasis and responsible for poor prognosis. EMT cancer cells modulate endothelial permeability in the invasive front and facilitate cancer cell intravasation, resulting in CTCs-mediated distant metastasis. Exosomes derived from cancer cells are key mediators of cancer-host intercommunication. However, the mechanism by which EMT-tumour cells-derived exosomes modulate vascular permeability and promote CTCs generation has remained unclear.MethodsExosomes isolation and purification were conducted by ultra-centrifugation. Exosomal miRNA was identified by sequencing followed by quantitative PCR. In vitro co-culture assay experiments were conducted to evaluate the effect of exosomal miR-27b-3p on the permeability of blood vessel endothelium. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) and RNA immunoprecipitation (RIP) were performed to investigate the underlying mechanism by which miR-27b-3p is packaged into exosomes. A mouse model was established to determine the role of exosomal miR-27b-3p in blood vessel permeability modulation in vivo.ResultsWe found that EMT-CRC cells attenuate the blood vessel barrier by transferring miR-27b-3p to human umbilical vein endothelial cells (HUVECs) in exosomes. Mechanically, miR-27b-3p atteuated the expression of vascular endothelial cadherin (VE-Cad) and p120 at the post-transcriptional level by binding to 3'-untranslated region of VE-Cad and p120 directly. The packaging of miR-27b-3p into exosomes was induced by heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which activated by STAT3. Clinically, miR-27b-3p up-regulated in CRC tissues. Plasma exosomal miR-27b-3p was positively correlated with malignant progression and CTC count in CRC patients. Our study reveals a novel mechanism by which EMT-CRC cells promote metastasis, increasing blood vessel permeability and facilitating the generation of CTCs.ConclusionExosomal miR-27b-3p secreted by EMT-CRC cells increases blood vessel permeability and facilitates the generation of CTCs. Exosomal miR-27b-3p may become a promising biomarker for CRC metastasis.

Project description:Thyroid cancer (TC) is a frequently occurring malignant tumor with a rising steadily incidence. microRNA (miRNA/miR)‑193a‑3p is an miRNA that is associated with tumors, playing a crucial role in the genesis and progression of various cancers. However, the expression levels of miR‑193a‑3p and its molecular mechanisms in TC remain to be elucidated. The present study aimed to probe the expression of miR‑193a‑3p and its clinical significance in TC, including its underlying molecular mechanisms. Microarray and RNA sequencing data gathered from three major databases, specifically Gene Expression Omnibus (GEO), ArrayExpress and The Cancer Genome Atlas (TCGA) databases, and the relevant data from the literature were used to examine miR‑193a‑3p expression. Meta‑analysis was also conducted to evaluate the association between clinicopathological parameters and miR‑193a‑3p in 510 TC and 59 normal samples from the TCGA database. miRWalk 3.0, and the TCGA and GEO databases were used to predict the candidate target genes of miR‑193a‑3p. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and protein‑protein interaction network enrichment analyses were conducted by using the predicted candidate target genes to investigate the underlying carcinogenic mechanisms. A dual luciferase assay was performed to validate the targeting regulatory association between the most important hub gene cyclin D1 (CCND1) and miR‑193a‑3p. miR‑193a‑3p expression was considerably downregulated in TC compared with in the non‑cancer controls (P<0.001). The area under the curve of the summary receiver operating characteristic was 0.80. Downregulation of miR‑193a‑3p was also significantly associated with age, sex and metastasis (P=0.020, 0.044 and 0.048, respectively). Bioinformatics analysis indicated that a low miR‑193a‑3p expression may augment CCND1 expression to affect the biological processes of TC. In addition, CCND1, as a straightforward target, was validated through a dual luciferase assay. miR‑193a‑3p and CCND1 may serve as prognostic biomarkers of TC. Finally, miR‑193a‑3p may possess a crucial role in the genesis and progression of TC by altering the CCND1 expression.

Dataset Information

Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p.

Publications

Targeting KRas-dependent tumour growth, circulating tumour cells and metastasis in vivo by clinically significant miR-193a-3p.

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