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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

P4HB is upregulated and miR-210 is downregulated in TMZ-resistant GBM cell lines. (A) Upregulation in the relative P4HB expression levels in TMZ-resistant GBM cell lines D54-R and U87-R when compared with those in the TMZ-sensitive D54-S and U87-S cells on qPCR. (B) Downregulations in miR-210 expression levels in D54-R and U87-R relative to those in D54-S and U87-S cells. (* = p < 0.05; *** = p < 0.001)
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Figure 1: P4HB is upregulated and miR-210 is downregulated in TMZ-resistant GBM cell lines. (A) Upregulation in the relative P4HB expression levels in TMZ-resistant GBM cell lines D54-R and U87-R when compared with those in the TMZ-sensitive D54-S and U87-S cells on qPCR. (B) Downregulations in miR-210 expression levels in D54-R and U87-R relative to those in D54-S and U87-S cells. (* = p < 0.05; *** = p < 0.001)

Mentions: To verify the involvement of P4HB in GBM chemoresistance, and that miR-210 would be its potential regulator, their intrinsic expressions were quantified. As expected, P4HB expression was upregulated in the TMZ-resistant cells D54-R and U87-R by approximately 6-folds and 5-folds, respectively, when compared with the parental cells D54-S and U87-S (Fig. 1A). Conversely, the TMZ-resistant D54-R and U87-R cells expressed lower levels of miR-210 in comparison to their TMZ-sensitive counterparts by 2-folds and 10-folds, respectively, suggesting that P4HB may potentially be under the regulation of miR-210 (Fig. 1B).


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)

P4HB is upregulated and miR-210 is downregulated in TMZ-resistant GBM cell lines. (A) Upregulation in the relative P4HB expression levels in TMZ-resistant GBM cell lines D54-R and U87-R when compared with those in the TMZ-sensitive D54-S and U87-S cells on qPCR. (B) Downregulations in miR-210 expression levels in D54-R and U87-R relative to those in D54-S and U87-S cells. (* = p < 0.05; *** = p < 0.001)
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Related In: Results  -  Collection

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Figure 1: P4HB is upregulated and miR-210 is downregulated in TMZ-resistant GBM cell lines. (A) Upregulation in the relative P4HB expression levels in TMZ-resistant GBM cell lines D54-R and U87-R when compared with those in the TMZ-sensitive D54-S and U87-S cells on qPCR. (B) Downregulations in miR-210 expression levels in D54-R and U87-R relative to those in D54-S and U87-S cells. (* = p < 0.05; *** = p < 0.001)
Mentions: To verify the involvement of P4HB in GBM chemoresistance, and that miR-210 would be its potential regulator, their intrinsic expressions were quantified. As expected, P4HB expression was upregulated in the TMZ-resistant cells D54-R and U87-R by approximately 6-folds and 5-folds, respectively, when compared with the parental cells D54-S and U87-S (Fig. 1A). Conversely, the TMZ-resistant D54-R and U87-R cells expressed lower levels of miR-210 in comparison to their TMZ-sensitive counterparts by 2-folds and 10-folds, respectively, suggesting that P4HB may potentially be under the regulation of miR-210 (Fig. 1B).

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