PMID- 32813021
OWN - NLM
STAT- MEDLINE
DCOM- 20210427
LR  - 20210427
IS  - 1523-5866 (Electronic)
IS  - 1522-8517 (Print)
IS  - 1522-8517 (Linking)
VI  - 23
IP  - 3
DP  - 2021 Mar 25
TI  - TGF-beta1 modulates temozolomide resistance in glioblastoma via altered microRNA 
      processing and elevated MGMT.
PG  - 435-446
LID - 10.1093/neuonc/noaa198 [doi]
AB  - 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-beta1) switches off miR-198 
      expression by repressing K-homology splicing regulatory protein (KSRP) expression 
      in epidermal keratinocytes. However, the underlying role of TGF-beta1 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-beta1-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-beta1 
      in temozolomide resistance. RESULTS: Overexpression of TGF-beta1 contributed to 
      temozolomide resistance in MGMT promoter hypomethylated glioblastoma cells in 
      vitro and in vivo. TGF-beta1 treatment reduced cellular MGMT levels through 
      suppressing the expression of miR-198. However, TGF-beta1 upregulation did not 
      affect KSRP expression in glioma cells. We identified and characterized 2 lncRNAs 
      (H19 and HOXD-AS2) that were upregulated by TGF-beta1 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-beta1 and lncRNAs on miR-198 
      and MGMT. Finally, we found that patients with low levels of TGF-beta1 or lncRNA 
      expression benefited from temozolomide therapy. CONCLUSIONS: Our results reveal 
      an underlying mechanism by which TGF-beta1 confers temozolomide resistance. 
      Furthermore, our findings suggest that a novel combination of temozolomide with a 
      TGF-beta inhibitor may serve as an effective therapy for glioblastomas.
CI  - (c) The Author(s) 2020. Published by Oxford University Press on behalf of the 
      Society for Neuro-Oncology.
FAU - Nie, Er
AU  - Nie E
AD  - Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, Jiangsu Province, PR China.
FAU - Jin, Xin
AU  - Jin X
AD  - Department of Medicine, Nanjing Gaochun People's Hospital, Nanjing, Jiangsu 
      Province, PR China.
FAU - Miao, Faan
AU  - Miao F
AD  - Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, Jiangsu Province, PR China.
FAU - Yu, Tianfu
AU  - Yu T
AD  - Department of Neurosurgery, The Affiliated Drum Tower Hospital, School of 
      Medicine, Nanjing University, Nanjing, Jiangsu Province, PR China.
FAU - Zhi, Tongle
AU  - Zhi T
AD  - Department of Neurosurgery, Yancheng City No. 1 People's Hospital, The 4th 
      Affiliated Hospital of Nantong University, Yancheng, Jiangsu Province, PR China.
FAU - Shi, Zhumei
AU  - Shi Z
AD  - Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, Jiangsu Province, PR China.
FAU - Wang, Yingyi
AU  - Wang Y
AD  - Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, Jiangsu Province, PR China.
FAU - Zhang, Junxia
AU  - Zhang J
AD  - Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, Jiangsu Province, PR China.
FAU - Xie, Manyi
AU  - Xie M
AD  - Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, Jiangsu Province, PR China.
FAU - You, Yongping
AU  - You Y
AD  - Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical 
      University, Nanjing, Jiangsu Province, PR China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Neuro Oncol
JT  - Neuro-oncology
JID - 100887420
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (MIRN198 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (Tumor Suppressor Proteins)
RN  - EC 2.1.1.- (DNA Modification Methylases)
RN  - EC 2.1.1.63 (MGMT protein, human)
RN  - EC 6.5.1.- (DNA Repair Enzymes)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Antineoplastic Agents, Alkylating/pharmacology/therapeutic use
MH  - Cell Line, Tumor
MH  - DNA Modification Methylases/genetics
MH  - DNA Repair Enzymes
MH  - Drug Resistance, Neoplasm/genetics
MH  - *Glioblastoma/drug therapy/genetics
MH  - Humans
MH  - *MicroRNAs/genetics
MH  - Temozolomide/pharmacology/therapeutic use
MH  - Transforming Growth Factor beta1/genetics/therapeutic use
MH  - Tumor Suppressor Proteins/genetics
PMC - PMC7992894
OTO - NOTNLM
OT  - KSRP
OT  - MGMT
OT  - TGF-beta1
OT  - glioblastoma
OT  - temozolomide resistance
EDAT- 2020/08/20 06:00
MHDA- 2021/04/28 06:00
PMCR- 2020/08/19
CRDT- 2020/08/20 06:00
PHST- 2020/08/20 06:00 [pubmed]
PHST- 2021/04/28 06:00 [medline]
PHST- 2020/08/20 06:00 [entrez]
PHST- 2020/08/19 00:00 [pmc-release]
AID - 5894410 [pii]
AID - noaa198 [pii]
AID - 10.1093/neuonc/noaa198 [doi]
PST - ppublish
SO  - Neuro Oncol. 2021 Mar 25;23(3):435-446. doi: 10.1093/neuonc/noaa198.