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PDGF induced microRNA alterations in cancer cells.

Shao M, Rossi S, Chelladurai B, Shimizu M, Ntukogu O, Ivan M, Calin GA, Matei D - Nucleic Acids Res. (2011)

Bottom Line: Here, we show by using microRNA (miR) arrays that PDGFs regulate the expression and function of miRs in glioblastoma and ovarian cancer cells.We demonstrate that PDGF regulates expression of some of its known targets (e.g. cyclin D1) through miR alterations and identify the epidermal growth factor receptor (EGFR) as a new PDGF-BB target.We show that its expression and function are repressed by PDGF-induced miR-146b and that mir-146b and EGFR correlate inversely in human glioblastomas.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Indiana University School of Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT
Platelet derived growth factor (PDGF) regulates gene transcription by binding to specific receptors. PDGF plays a critical role in oncogenesis in brain and other tumors, regulates angiogenesis, and remodels the stroma in physiologic conditions. Here, we show by using microRNA (miR) arrays that PDGFs regulate the expression and function of miRs in glioblastoma and ovarian cancer cells. The two PDGF ligands AA and BB affect expression of several miRs in ligand-specific manner; the most robust changes consisting of let-7d repression by PDGF-AA and miR-146b induction by PDGF-BB. Induction of miR-146b by PDGF-BB is modulated via MAPK-dependent induction of c-fos. We demonstrate that PDGF regulates expression of some of its known targets (e.g. cyclin D1) through miR alterations and identify the epidermal growth factor receptor (EGFR) as a new PDGF-BB target. We show that its expression and function are repressed by PDGF-induced miR-146b and that mir-146b and EGFR correlate inversely in human glioblastomas. We propose that PDGF-regulated gene transcription involves alterations in non-coding RNAs and provide evidence for a miR-dependent feedback mechanism balancing growth factor receptor signaling in cancer cells.

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Hierarchical clustering demonstrates specific effects of PDGF-AA and PDGF–BB on miR expression in U118 cells. (A) Differential expression of miRs is induced by PDGF-AA and PDGF-BB at different timepoints. Among other miRs, let-7d is suppressed by PDGF-AA (see arrow). (B) Effects of PDGF-BB on miR expression (0 versus 12 h). Among other miRs, miR-146b is induced by PDGF-BB (see arrow). qPCR quantifies let-7d expression levels in U118 MG (C), C272/hTert/E7 (D), SH-SY5Y (E) and WI38 cells (F) after PDGF-AA treatment. Statistical significance is marked by asterisks.
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Figure 1: Hierarchical clustering demonstrates specific effects of PDGF-AA and PDGF–BB on miR expression in U118 cells. (A) Differential expression of miRs is induced by PDGF-AA and PDGF-BB at different timepoints. Among other miRs, let-7d is suppressed by PDGF-AA (see arrow). (B) Effects of PDGF-BB on miR expression (0 versus 12 h). Among other miRs, miR-146b is induced by PDGF-BB (see arrow). qPCR quantifies let-7d expression levels in U118 MG (C), C272/hTert/E7 (D), SH-SY5Y (E) and WI38 cells (F) after PDGF-AA treatment. Statistical significance is marked by asterisks.

Mentions: Cluster analysis shows global differences between miRs altered by PDGF-AA and PDGF-BB, let-7d being one of the miRs repressed by PDGF-AA (Figure 1A) and mir-146b being one of the miRs induced by PDGF-BB (Figure 1B). These two miRs were studied in further detail in subsequent analyses. Supervised and unsupervised PCA miR classification was performed for samples stimulated with PDGF-AA or PDGF-BB at different timepoints versus un-stimulated samples. Analyses summarized in Supplementary Figure S1A and B demonstrate significant differences in miR expression patterns induced by the two PDGFs versus un-stimulated cells. Likewise PCA was used to classify miRs altered by PDGF-AA versus PDGF-BB (Supplementary Figure S1C–F) demonstrating discriminatory miR profiles elicited by the two PDGF ligands. Selected miRs emerging from the microarray analysis were confirmed by qPCR. The U118MG, C272/hTert/E7 and WI38 cells express both PDGF receptor subunits, while U87MG cells express predominantly PDGFR-β (Supplementary Figure S2A). Supplementary Figure S2 includes selected validation studies confirming by qPCR miR alterations induced by PDGF, such as miR-106b up-regulation by PDGF-BB.Figure 1.


PDGF induced microRNA alterations in cancer cells.

Shao M, Rossi S, Chelladurai B, Shimizu M, Ntukogu O, Ivan M, Calin GA, Matei D - Nucleic Acids Res. (2011)

Hierarchical clustering demonstrates specific effects of PDGF-AA and PDGF–BB on miR expression in U118 cells. (A) Differential expression of miRs is induced by PDGF-AA and PDGF-BB at different timepoints. Among other miRs, let-7d is suppressed by PDGF-AA (see arrow). (B) Effects of PDGF-BB on miR expression (0 versus 12 h). Among other miRs, miR-146b is induced by PDGF-BB (see arrow). qPCR quantifies let-7d expression levels in U118 MG (C), C272/hTert/E7 (D), SH-SY5Y (E) and WI38 cells (F) after PDGF-AA treatment. Statistical significance is marked by asterisks.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Figure 1: Hierarchical clustering demonstrates specific effects of PDGF-AA and PDGF–BB on miR expression in U118 cells. (A) Differential expression of miRs is induced by PDGF-AA and PDGF-BB at different timepoints. Among other miRs, let-7d is suppressed by PDGF-AA (see arrow). (B) Effects of PDGF-BB on miR expression (0 versus 12 h). Among other miRs, miR-146b is induced by PDGF-BB (see arrow). qPCR quantifies let-7d expression levels in U118 MG (C), C272/hTert/E7 (D), SH-SY5Y (E) and WI38 cells (F) after PDGF-AA treatment. Statistical significance is marked by asterisks.
Mentions: Cluster analysis shows global differences between miRs altered by PDGF-AA and PDGF-BB, let-7d being one of the miRs repressed by PDGF-AA (Figure 1A) and mir-146b being one of the miRs induced by PDGF-BB (Figure 1B). These two miRs were studied in further detail in subsequent analyses. Supervised and unsupervised PCA miR classification was performed for samples stimulated with PDGF-AA or PDGF-BB at different timepoints versus un-stimulated samples. Analyses summarized in Supplementary Figure S1A and B demonstrate significant differences in miR expression patterns induced by the two PDGFs versus un-stimulated cells. Likewise PCA was used to classify miRs altered by PDGF-AA versus PDGF-BB (Supplementary Figure S1C–F) demonstrating discriminatory miR profiles elicited by the two PDGF ligands. Selected miRs emerging from the microarray analysis were confirmed by qPCR. The U118MG, C272/hTert/E7 and WI38 cells express both PDGF receptor subunits, while U87MG cells express predominantly PDGFR-β (Supplementary Figure S2A). Supplementary Figure S2 includes selected validation studies confirming by qPCR miR alterations induced by PDGF, such as miR-106b up-regulation by PDGF-BB.Figure 1.

Bottom Line: Here, we show by using microRNA (miR) arrays that PDGFs regulate the expression and function of miRs in glioblastoma and ovarian cancer cells.We demonstrate that PDGF regulates expression of some of its known targets (e.g. cyclin D1) through miR alterations and identify the epidermal growth factor receptor (EGFR) as a new PDGF-BB target.We show that its expression and function are repressed by PDGF-induced miR-146b and that mir-146b and EGFR correlate inversely in human glioblastomas.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Indiana University School of Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

ABSTRACT
Platelet derived growth factor (PDGF) regulates gene transcription by binding to specific receptors. PDGF plays a critical role in oncogenesis in brain and other tumors, regulates angiogenesis, and remodels the stroma in physiologic conditions. Here, we show by using microRNA (miR) arrays that PDGFs regulate the expression and function of miRs in glioblastoma and ovarian cancer cells. The two PDGF ligands AA and BB affect expression of several miRs in ligand-specific manner; the most robust changes consisting of let-7d repression by PDGF-AA and miR-146b induction by PDGF-BB. Induction of miR-146b by PDGF-BB is modulated via MAPK-dependent induction of c-fos. We demonstrate that PDGF regulates expression of some of its known targets (e.g. cyclin D1) through miR alterations and identify the epidermal growth factor receptor (EGFR) as a new PDGF-BB target. We show that its expression and function are repressed by PDGF-induced miR-146b and that mir-146b and EGFR correlate inversely in human glioblastomas. We propose that PDGF-regulated gene transcription involves alterations in non-coding RNAs and provide evidence for a miR-dependent feedback mechanism balancing growth factor receptor signaling in cancer cells.

Show MeSH
Related in: MedlinePlus