TGF-β1 modulates temozolomide resistance in glioblastoma via altered microRNA processing and elevated MGMT

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Abstract

Background

Our previous studies have indicated that miR-198 reduces cellular methylguanine DNA methyltransferase (MGMT) levels to enhance temozolomide sensitivity. Transforming growth factor beta 1 (TGF-β1) switches off miR-198 expression by repressing K-homology splicing regulatory protein (KSRP) expression in epidermal keratinocytes. However, the underlying role of TGF-β1 in temozolomide resistance has remained unknown.

Methods

The distribution of KSRP was detected by western blotting and immunofluorescence. Microarray analysis was used to compare the levels of long noncoding RNAs (lncRNAs) between TGF-β1–treated and untreated cells. RNA immunoprecipitation was performed to verify the relationship between RNAs and KSRP. Flow cytometry and orthotopic and subcutaneous xenograft tumor models were used to determine the function of TGF-β1 in temozolomide resistance.

Results

Overexpression of TGF-β1 contributed to temozolomide resistance in MGMT promoter hypomethylated glioblastoma cells in vitro and in vivo. TGF-β1 treatment reduced cellular MGMT levels through suppressing the expression of miR-198. However, TGF-β1 upregulation did not affect KSRP expression in glioma cells. We identified and characterized 2 lncRNAs (H19 and HOXD-AS2) that were upregulated by TGF-β1 through Smad signaling. H19 and HOXD-AS2 exhibited competitive binding to KSRP and prevented KSRP from binding to primary miR-198, thus decreasing miR-198 expression. HOXD-AS2 or H19 upregulation strongly promoted temozolomide resistance and MGMT expression. Moreover, KSRP depletion abrogated the effects of TGF-β1 and lncRNAs on miR-198 and MGMT. Finally, we found that patients with low levels of TGF-β1 or lncRNA expression benefited from temozolomide therapy.

Conclusions

Our results reveal an underlying mechanism by which TGF-β1 confers temozolomide resistance. Furthermore, our findings suggest that a novel combination of temozolomide with a TGF-β inhibitor may serve as an effective therapy for glioblastomas.

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Most cited references 32

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Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

Roger Stupp, Warren P Mason, Martin van den Bent … (2005)

Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.

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MGMT gene silencing and benefit from temozolomide in glioblastoma.

Monika E Hegi, Annie-Claire Diserens, Thierry Gorlia … (2005)

Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit. Copyright 2005 Massachusetts Medical Society.

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TGFbeta in Cancer.

Joan Massagué (2008)

The transforming growth factor beta (TGFbeta) signaling pathway is a key player in metazoan biology, and its misregulation can result in tumor development. The regulatory cytokine TGFbeta exerts tumor-suppressive effects that cancer cells must elude for malignant evolution. Yet, paradoxically, TGFbeta also modulates processes such as cell invasion, immune regulation, and microenvironment modification that cancer cells may exploit to their advantage. Consequently, the output of a TGFbeta response is highly contextual throughout development, across different tissues, and also in cancer. The mechanistic basis and clinical relevance of TGFbeta's role in cancer is becoming increasingly clear, paving the way for a better understanding of the complexity and therapeutic potential of this pathway.

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Author and article information

Journal

Journal ID (nlm-ta): Neuro Oncol

Journal ID (iso-abbrev): Neuro Oncol

Journal ID (publisher-id): neuonc

Title: Neuro-Oncology

Publisher: Oxford University Press (US )

ISSN (Print): 1522-8517

ISSN (Electronic): 1523-5866

Publication date Collection: March 2021

Publication date (Electronic): 19 August 2020

Publication date PMC-release: 19 August 2020

Volume: 23

Issue: 3

Pages: 435-446

Affiliations

[1 ] Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University , Xuzhou, Jiangsu Province, PR China

[2 ] Department of Medicine, Nanjing Gaochun People’s Hospital , Nanjing, Jiangsu Province, PR China

[3 ] Department of Neurosurgery, The Affiliated Drum Tower Hospital, School of Medicine, Nanjing University , Nanjing, Jiangsu Province, PR China

[4 ] Department of Neurosurgery, Yancheng City No. 1 People’s Hospital, The 4th Affiliated Hospital of Nantong University , Yancheng, Jiangsu Province, PR China

[5 ] Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu Province, PR China

Author notes

Corresponding Authors: Junxia Zhang, M.D., Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, China ( zjx2032@ 123456126.com ); Manyi Xie, M.D., Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, 99 Huaihai West Road, Xuzhou 221000, Jiangsu Province, China ( aman_80@ 123456126.com ); Yongping You, Ph.D., Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, China ( yypl9@ 123456njmu.edu.cn ).

These authors contributed equally to the manuscript.

Article

Publisher ID: noaa198

DOI: 10.1093/neuonc/noaa198

PMC ID: 7992894

PubMed ID: 32813021

SO-VID: 99329dde-2ebd-421c-bd14-a08af0f65ea9

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date: 31 October 2020

Page count

Pages: 12

Funding

Funded by: National Natural Science Foundation of China, DOI 10.13039/501100001809;

Award ID: 81802490

Award ID: 81772679

Funded by: National Key Research and Development Plan;

Award ID: 2016YFC0902500

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TGF-β1 modulates temozolomide resistance in glioblastoma via altered microRNA processing and elevated MGMT

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Most cited references 32

Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

MGMT gene silencing and benefit from temozolomide in glioblastoma.

TGFbeta in Cancer.

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