microRNA-210-3p depletion by CRISPR/Cas9 promoted tumorigenesis through revival of TWIST1 in renal cell carcinoma

Previous studies showed that five miRNAs (miR-885-5p, miR-1274, miR-210-3p, miR-224 and miR-1290) were upregulated the most in clear cell renal cell carcinoma (ccRCC). Our focus was to understand from a clinical standpoint the functional consequences of upregulating miR-210-3p. Towards this, we util...

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Bibliographic Details
Published in:Oncotarget 2017-03, Vol.8 (13), p.20881-20894
Main Authors: Yoshino, Hirofumi, Yonemori, Masaya, Miyamoto, Kazutaka, Tatarano, Syuichi, Kofuji, Satoshi, Nohata, Nijiro, Nakagawa, Masayuki, Enokida, Hideki
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Carcinoma, Renal Cell - genetics
Carcinoma, Renal Cell - metabolism
Carcinoma, Renal Cell - pathology
Cell Movement
Cell Proliferation
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Cell Transformation, Neoplastic - pathology
CRISPR-Cas Systems - genetics
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic
Humans
Kidney Neoplasms - genetics
Kidney Neoplasms - metabolism
Kidney Neoplasms - pathology
Mice
Mice, Inbred BALB C
Mice, Nude
MicroRNAs - antagonists & inhibitors
MicroRNAs - genetics
Neoplasm Staging
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Prognosis
Research Paper
Survival Rate
Tumor Cells, Cultured
Twist-Related Protein 1 - genetics
Twist-Related Protein 1 - metabolism
Xenograft Model Antitumor Assays
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Summary:Previous studies showed that five miRNAs (miR-885-5p, miR-1274, miR-210-3p, miR-224 and miR-1290) were upregulated the most in clear cell renal cell carcinoma (ccRCC). Our focus was to understand from a clinical standpoint the functional consequences of upregulating miR-210-3p. Towards this, we utilized the CRISPR/Cas9 gene editing system to deplete miR-210-3p in RCC cell lines (786-o, A498 and Caki2) and characterized the outcomes. We observed that miR-210-3p depletion dramatically increased tumorigenesis, including altering the morphology of A498 and Caki2 cells in a manner characteristic of epithelial-mesenchymal transition (EMT). These results were corroborated by in vivo xenograft studies, which showed enhanced growth of tumors from miR-210-3p-depleted A498 cells. We identified Twist-related protein 1 (TWIST1) as a key target of miR-210-3p. Analysis of the ccRCC patient data in The Cancer Genome Atlas database showed a negative correlation between miR-210-3p and TWIST1 expression. High TWIST1 and low miR-210-3p expression associated with poorer overall and disease-free survival as compared to low TWIST1 and high miR-210-3p expression. These findings suggest that renal cell carcinoma progression is promoted by TWIST1 suppression mediated by miR-210-3p.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.14930