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MicroRNA-210 and Endoplasmic Reticulum Chaperones in the Regulation of Chemoresistance in Glioblastoma.

Lee D, Sun S, Zhang XQ, Zhang PD, Ho AS, Kiang KM, Fung CF, Lui WM, Leung GK - J Cancer (2015)

Bottom Line: We found that miRNA-210 (miR-210) was P4HB-targeting and was highly downregulated in TMZ-resistant GBM cells.Forced overexpression of miR-210 led to P4HB downregulation and a reduction in TMZ-resistance.The findings have important translational implications in suggesting new directions of future studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.

ABSTRACT
Glioblastoma multiforme (GBM) is the commonest primary brain tumour in adults characterized by relentless recurrence due to resistance towards the standard chemotherapeutic agent temozolomide (TMZ). Prolyl 4-hydroxylase, beta polypeptide (P4HB), an endoplasmic reticulum (ER) chaperone, is known to be upregulated in TMZ-resistant GBM cells. MicroRNAs (miRNAs) are non-protein-coding transcripts that may play important roles in GBM chemoresistance. We surmised that miRNA dysregulations may contribute to P4HB upregulation, hence chemoresistance. We found that miRNA-210 (miR-210) was P4HB-targeting and was highly downregulated in TMZ-resistant GBM cells. Forced overexpression of miR-210 led to P4HB downregulation and a reduction in TMZ-resistance. A reciprocal relationship between their expressions was also verified in clinical glioma specimens. Our study is the first to demonstrate a potential link between miR-210 and ER chaperone in determining chemosensitivity in GBM. The findings have important translational implications in suggesting new directions of future studies.

No MeSH data available.


Related in: MedlinePlus

MiR-210 upregulation may reduce chemoresistance in GBM cells. A decrease in IC50 of TMZ for cells with miR-210 overexpression (“+”) relative to its respective negative controls (“-“) in all four GBM cell lines used by MTT cell proliferation assay.
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Figure 4: MiR-210 upregulation may reduce chemoresistance in GBM cells. A decrease in IC50 of TMZ for cells with miR-210 overexpression (“+”) relative to its respective negative controls (“-“) in all four GBM cell lines used by MTT cell proliferation assay.

Mentions: With its effect of downregulating P4HB expression, we then examined whether miR-210 overexpression would diminish TMZ-resistance using the MTT cell proliferation assay (Fig. 4). Except for U87-R, the IC50 of TMZ for cells transfected with negative controls was around 2000 μM. With miR-210 overexpression, the IC50 was reduced to about 200 μM and 500 μM for the D54-S and U87-S cells, respectively, and at about 500 μM and 600 μM for the TMZ-resistant D54-R and U87-R cells, respectively. The overall findings were consistent with the suggestion that P4HB would confer TMZ resistance in GBM, and that miR-210 overexpression may downregulate P4HB expression, resulting in greater response to TMZ cytotoxicity.


MicroRNA-210 and Endoplasmic Reticulum Chaperones in the Regulation of Chemoresistance in Glioblastoma.

Lee D, Sun S, Zhang XQ, Zhang PD, Ho AS, Kiang KM, Fung CF, Lui WM, Leung GK - J Cancer (2015)

MiR-210 upregulation may reduce chemoresistance in GBM cells. A decrease in IC50 of TMZ for cells with miR-210 overexpression (“+”) relative to its respective negative controls (“-“) in all four GBM cell lines used by MTT cell proliferation assay.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4317757&req=5

Figure 4: MiR-210 upregulation may reduce chemoresistance in GBM cells. A decrease in IC50 of TMZ for cells with miR-210 overexpression (“+”) relative to its respective negative controls (“-“) in all four GBM cell lines used by MTT cell proliferation assay.
Mentions: With its effect of downregulating P4HB expression, we then examined whether miR-210 overexpression would diminish TMZ-resistance using the MTT cell proliferation assay (Fig. 4). Except for U87-R, the IC50 of TMZ for cells transfected with negative controls was around 2000 μM. With miR-210 overexpression, the IC50 was reduced to about 200 μM and 500 μM for the D54-S and U87-S cells, respectively, and at about 500 μM and 600 μM for the TMZ-resistant D54-R and U87-R cells, respectively. The overall findings were consistent with the suggestion that P4HB would confer TMZ resistance in GBM, and that miR-210 overexpression may downregulate P4HB expression, resulting in greater response to TMZ cytotoxicity.

Bottom Line: We found that miRNA-210 (miR-210) was P4HB-targeting and was highly downregulated in TMZ-resistant GBM cells.Forced overexpression of miR-210 led to P4HB downregulation and a reduction in TMZ-resistance.The findings have important translational implications in suggesting new directions of future studies.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong.

ABSTRACT
Glioblastoma multiforme (GBM) is the commonest primary brain tumour in adults characterized by relentless recurrence due to resistance towards the standard chemotherapeutic agent temozolomide (TMZ). Prolyl 4-hydroxylase, beta polypeptide (P4HB), an endoplasmic reticulum (ER) chaperone, is known to be upregulated in TMZ-resistant GBM cells. MicroRNAs (miRNAs) are non-protein-coding transcripts that may play important roles in GBM chemoresistance. We surmised that miRNA dysregulations may contribute to P4HB upregulation, hence chemoresistance. We found that miRNA-210 (miR-210) was P4HB-targeting and was highly downregulated in TMZ-resistant GBM cells. Forced overexpression of miR-210 led to P4HB downregulation and a reduction in TMZ-resistance. A reciprocal relationship between their expressions was also verified in clinical glioma specimens. Our study is the first to demonstrate a potential link between miR-210 and ER chaperone in determining chemosensitivity in GBM. The findings have important translational implications in suggesting new directions of future studies.

No MeSH data available.


Related in: MedlinePlus