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The Essential Role of H19 Contributing to Cisplatin Resistance by Regulating
Glutathione Metabolism in High-Grade Serous Ovarian Cancer
#MMPMID27193186
Zheng ZG
; Xu H
; Suo SS
; Xu XL
; Ni MW
; Gu LH
; Chen W
; Wang LY
; Zhao Y
; Tian B
; Hua YJ
Sci Rep
2016[May]; 6
(?): 26093
PMID27193186
show ga
Primary and acquired drug resistance is one of the main obstacles encountered in
high-grade serous ovarian cancer (HGSC) chemotherapy. Cisplatin induces DNA
damage through cross-linking and long integrated non-coding RNAs (lincRNAs) play
an important role in chemical induced DNA-damage response, which suggests that
lincRNAs may be also associated with cisplatin resistance. However, the mechanism
of long integrated non-coding RNAs (lincRNAs) acting on cisplatin resistance is
not well understood. Here, we showed that expression of lin-RECK-3, H19, LUCAT1,
LINC00961, and linc-CARS2-2 was enhanced in cisplatin-resistant A2780-DR cells,
while transcriptome sequencing showed decreased Linc-TNFRSF19-1 and LINC00515
expression. Additionally, we verified that different H19 expression levels in
HGSC tissues showed strong correlation with cancer recurrence. H19 knockdown in
A2780-DR cells resulted in recovery of cisplatin sensitivity in vitro and in
vivo. Quantitative proteomics analysis indicated that six NRF2-targeted proteins,
including NQO1, GSR, G6PD, GCLC, GCLM and GSTP1 involved in the glutathione
metabolism pathway, were reduced in H19-knockdown cells. Furthermore,
H19-knockdown cells were markedly more sensitive to hydrogen-peroxide treatment
and exhibited lower glutathione levels. Our results reveal a previously unknown
link between H19 and glutathione metabolism in the regulation of cancer-drug
resistance.
|*Drug Resistance, Neoplasm
[MESH]
|Antineoplastic Agents/*pharmacology
[MESH]
|Cell Line, Tumor
[MESH]
|Cisplatin/*pharmacology
[MESH]
|Female
[MESH]
|Gene Expression Profiling
[MESH]
|Glutathione/*metabolism
[MESH]
|Humans
[MESH]
|Neoplasms, Cystic, Mucinous, and Serous/*pathology
[MESH]
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