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MiR-203 downregulation is responsible for chemoresistance in human glioblastoma by promoting epithelial-mesenchymal transition via SNAI2.

Liao H, Bai Y, Qiu S, Zheng L, Huang L, Liu T, Wang X, Liu Y, Xu N, Yan X, Guo H - Oncotarget (2015)

Bottom Line: We found that miR-203 expression was significantly lower in imatinib-resistant GBM cells (U251AR, U87AR) that underwent EMT than in their parental cells (U251, U87).Ectopic expression of miR-203 with miRNA mimics effectively reversed EMT in U251AR and U87AR cells, and sensitized them to chemotherapy, whereas inhibition of miR-203 in the sensitive lines with antisense oligonucleotides induced EMT and conferred chemoresistance.SNAI2 was identified as a direct target gene of miR-203.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Repair and Regeneration of Guangdong, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

ABSTRACT
Epithelial-mesenchymal transition (EMT) has been recognized as a key element of cell migration, invasion, and drug resistance in several types of cancer. In this study, our aim was to clarify microRNAs (miRNAs)-related mechanisms underlying EMT followed by acquired resistance to chemotherapy in glioblastoma (GBM). We used multiple methods to achieve our goal including microarray analysis, qRT-PCR, western blotting analysis, loss/gain-of-function analysis, luciferase assays, drug sensitivity assays, wound-healing assay and invasion assay. We found that miR-203 expression was significantly lower in imatinib-resistant GBM cells (U251AR, U87AR) that underwent EMT than in their parental cells (U251, U87). Ectopic expression of miR-203 with miRNA mimics effectively reversed EMT in U251AR and U87AR cells, and sensitized them to chemotherapy, whereas inhibition of miR-203 in the sensitive lines with antisense oligonucleotides induced EMT and conferred chemoresistance. SNAI2 was identified as a direct target gene of miR-203. The knockdown of SNAI2 by short hairpin RNA (shRNA) inhibited EMT and drug resistance. In GBM patients, miR-203 expression was inversely related to SNAI2 expression, and those tumors with low expression of miR-203 experienced poorer clinical outcomes. Our findings indicate that re-expression of miR-203 or targeting SNAI2 might serve as potential therapeutic approaches to overcome chemotherapy resistance in GBM.

No MeSH data available.


Related in: MedlinePlus

MicroRNA dysregulation in the imatinib resistant GBM cell line U87AR(A) Heatmap representation of differentially expressed microRNAs in the U87 and U87AR cells. Rows, miRNA; columns, independent biological replicates. Upregulated microRNAs are shown in red, while downregulated microRNAs are shown in green. (B) Differentially expressed microRNAs between U87 and U87AR cells.
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Figure 2: MicroRNA dysregulation in the imatinib resistant GBM cell line U87AR(A) Heatmap representation of differentially expressed microRNAs in the U87 and U87AR cells. Rows, miRNA; columns, independent biological replicates. Upregulated microRNAs are shown in red, while downregulated microRNAs are shown in green. (B) Differentially expressed microRNAs between U87 and U87AR cells.

Mentions: To screen miRNAs that are potentially involved in the acquisition of drug resistance and induction of EMT, we performed microarray miRNA analysis on U87AR and its parental U87 cells. Microarray analysis revealed a significant downregulation of 11 miRNAs and upregulation of 14 miRNAs in U87AR compared with U87 cells (Figure 2A, B).


MiR-203 downregulation is responsible for chemoresistance in human glioblastoma by promoting epithelial-mesenchymal transition via SNAI2.

Liao H, Bai Y, Qiu S, Zheng L, Huang L, Liu T, Wang X, Liu Y, Xu N, Yan X, Guo H - Oncotarget (2015)

MicroRNA dysregulation in the imatinib resistant GBM cell line U87AR(A) Heatmap representation of differentially expressed microRNAs in the U87 and U87AR cells. Rows, miRNA; columns, independent biological replicates. Upregulated microRNAs are shown in red, while downregulated microRNAs are shown in green. (B) Differentially expressed microRNAs between U87 and U87AR cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496192&req=5

Figure 2: MicroRNA dysregulation in the imatinib resistant GBM cell line U87AR(A) Heatmap representation of differentially expressed microRNAs in the U87 and U87AR cells. Rows, miRNA; columns, independent biological replicates. Upregulated microRNAs are shown in red, while downregulated microRNAs are shown in green. (B) Differentially expressed microRNAs between U87 and U87AR cells.
Mentions: To screen miRNAs that are potentially involved in the acquisition of drug resistance and induction of EMT, we performed microarray miRNA analysis on U87AR and its parental U87 cells. Microarray analysis revealed a significant downregulation of 11 miRNAs and upregulation of 14 miRNAs in U87AR compared with U87 cells (Figure 2A, B).

Bottom Line: We found that miR-203 expression was significantly lower in imatinib-resistant GBM cells (U251AR, U87AR) that underwent EMT than in their parental cells (U251, U87).Ectopic expression of miR-203 with miRNA mimics effectively reversed EMT in U251AR and U87AR cells, and sensitized them to chemotherapy, whereas inhibition of miR-203 in the sensitive lines with antisense oligonucleotides induced EMT and conferred chemoresistance.SNAI2 was identified as a direct target gene of miR-203.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Neurosurgery Institute of Guangdong, Key Laboratory on Brain Function Repair and Regeneration of Guangdong, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

ABSTRACT
Epithelial-mesenchymal transition (EMT) has been recognized as a key element of cell migration, invasion, and drug resistance in several types of cancer. In this study, our aim was to clarify microRNAs (miRNAs)-related mechanisms underlying EMT followed by acquired resistance to chemotherapy in glioblastoma (GBM). We used multiple methods to achieve our goal including microarray analysis, qRT-PCR, western blotting analysis, loss/gain-of-function analysis, luciferase assays, drug sensitivity assays, wound-healing assay and invasion assay. We found that miR-203 expression was significantly lower in imatinib-resistant GBM cells (U251AR, U87AR) that underwent EMT than in their parental cells (U251, U87). Ectopic expression of miR-203 with miRNA mimics effectively reversed EMT in U251AR and U87AR cells, and sensitized them to chemotherapy, whereas inhibition of miR-203 in the sensitive lines with antisense oligonucleotides induced EMT and conferred chemoresistance. SNAI2 was identified as a direct target gene of miR-203. The knockdown of SNAI2 by short hairpin RNA (shRNA) inhibited EMT and drug resistance. In GBM patients, miR-203 expression was inversely related to SNAI2 expression, and those tumors with low expression of miR-203 experienced poorer clinical outcomes. Our findings indicate that re-expression of miR-203 or targeting SNAI2 might serve as potential therapeutic approaches to overcome chemotherapy resistance in GBM.

No MeSH data available.


Related in: MedlinePlus