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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

Downregulation of miR-203 correlates with chemotherapy resistance and poor patient survival in GBM(A) Expression of SNAI2 and E-cadherin in resected human GBM specimen was assessed by immunohistochemistry assay. Scale bar, 100 μm. (B) Average expression levels of SNAI2 and E-cadherin in human primary GBM specimens and relapsed GBM tissues. (C) The expression of miR-203 was significantly reduced in relapsed GBM patients. (D) Kaplan-Meier overall survival curve according to miR-203 expression levels in GBM patients (p = 0.0017). *P < 0.05, **P < 0.01.
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Figure 7: Downregulation of miR-203 correlates with chemotherapy resistance and poor patient survival in GBM(A) Expression of SNAI2 and E-cadherin in resected human GBM specimen was assessed by immunohistochemistry assay. Scale bar, 100 μm. (B) Average expression levels of SNAI2 and E-cadherin in human primary GBM specimens and relapsed GBM tissues. (C) The expression of miR-203 was significantly reduced in relapsed GBM patients. (D) Kaplan-Meier overall survival curve according to miR-203 expression levels in GBM patients (p = 0.0017). *P < 0.05, **P < 0.01.

Mentions: To further evaluated the clinical significance of miR-203 expression in chemotherapeutic resistance and patient prognosis of GBM, SNAI2 expression was detected in tissues from 35 cases of patients with primary GBM and 16 cases of patients with relapsed GBM by immunohistochemistry. We found that the expression level of SNAI2 in relapsed GBM patients with treatment of temozolomide for 6 months was higher than that in primary GBM patients without treatment of temozolomide (Figure 7A). In contrast, E-cadherin was lowly expressed in the relapsed GBM patients (Figure 7A). Furthermore, qRT-PCR showed that the mRNA level of SNAI2 was significantly increased in relapsed GBM samples, whereas E-cadherin mRNA level was reduced compared to primary GBM tissues (Figure 7B). Finally, we found that the expression of miR-203 was significantly reduced (p=0.0026) in relapsed GBM tissues (Figure 7C). Moreover, patients with higher expression levels of miR-203 survived longer (p = 0.0017) than patients with lower expression levels (Figure 7D).


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)

Downregulation of miR-203 correlates with chemotherapy resistance and poor patient survival in GBM(A) Expression of SNAI2 and E-cadherin in resected human GBM specimen was assessed by immunohistochemistry assay. Scale bar, 100 μm. (B) Average expression levels of SNAI2 and E-cadherin in human primary GBM specimens and relapsed GBM tissues. (C) The expression of miR-203 was significantly reduced in relapsed GBM patients. (D) Kaplan-Meier overall survival curve according to miR-203 expression levels in GBM patients (p = 0.0017). *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Downregulation of miR-203 correlates with chemotherapy resistance and poor patient survival in GBM(A) Expression of SNAI2 and E-cadherin in resected human GBM specimen was assessed by immunohistochemistry assay. Scale bar, 100 μm. (B) Average expression levels of SNAI2 and E-cadherin in human primary GBM specimens and relapsed GBM tissues. (C) The expression of miR-203 was significantly reduced in relapsed GBM patients. (D) Kaplan-Meier overall survival curve according to miR-203 expression levels in GBM patients (p = 0.0017). *P < 0.05, **P < 0.01.
Mentions: To further evaluated the clinical significance of miR-203 expression in chemotherapeutic resistance and patient prognosis of GBM, SNAI2 expression was detected in tissues from 35 cases of patients with primary GBM and 16 cases of patients with relapsed GBM by immunohistochemistry. We found that the expression level of SNAI2 in relapsed GBM patients with treatment of temozolomide for 6 months was higher than that in primary GBM patients without treatment of temozolomide (Figure 7A). In contrast, E-cadherin was lowly expressed in the relapsed GBM patients (Figure 7A). Furthermore, qRT-PCR showed that the mRNA level of SNAI2 was significantly increased in relapsed GBM samples, whereas E-cadherin mRNA level was reduced compared to primary GBM tissues (Figure 7B). Finally, we found that the expression of miR-203 was significantly reduced (p=0.0026) in relapsed GBM tissues (Figure 7C). Moreover, patients with higher expression levels of miR-203 survived longer (p = 0.0017) than patients with lower expression levels (Figure 7D).

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