Publication: LHPP promotes the intracellular reactive oxygen species accumulation and sensitivity of gastric cancer to cisplatin via JNK and p38 MAPK pathways
Authors
Gao, Kai ; Yin, Ning ; Shen, Zhaolong ; Li, Qiqing ; Chen, Peng ; Yang, Kaiyan
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Publisher
Universidad de Murcia, Departamento de Biologia Celular e Histiologia
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DOI
https://doi.org/10.14670/HH-18-570
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info:eu-repo/semantics/article
Description
Abstract
Background. Cisplatin is the first-line
chemotherapy drug for the treatment of gastric cancer
(GC) patients. However, GC patients who are resistant to
cisplatin often do not benefit from it. Therefore, finding
a key molecule that affects cisplatin sensitivity is
expected to enhance the efficacy of cisplatin in GC
treatment.
Methods. The human GC cell lines SGC-7901 and
BGC-823 were used. The protein chip array was used to
screen the cisplatin-resistance genes from the complete
response and non-complete response GC patients’
tissues, then, the differential gene expression analysis,
GO function annotation analysis, and KEGG pathway
enrichment analysis were performed. The GC tissue chip
in the GEO database was analyzed to screen the target
gene. Flow cytometry, Hoechst 33342 staining assay,
Western Blot, MTT, tumor sphere formation, cell cycle,
and apoptosis assays were performed to explore the
effect of Phospholysine Phosphohistidine Inorganic
Pyrophosphate Phosphatase (LHPP) on the apoptosis,
stemness, and reactive oxygen species (ROS)
accumulation of cisplatin-resistant GC cells treated with
cisplatin. In vivo, the cisplatin-resistant GC cell lines
transfected with pcDNA-LHPP or si-LHPP were injected
subcutaneously into mice to construct GC subcutaneous
xenograft GC models.
Results. Based on protein chip array and
bioinformatics analysis, it was found that LHPP is the
core molecule in the cisplatin resistance regulatory
network in GC, and its expression is down-regulated in
GC cisplatin-resistant tissues and cells. In vitro and in
vivo experimental results show that the up-regulated
expression of LHPP is closely related to the increase in
sensitivity of GC to cisplatin. Mechanically, we found
that overexpression of LHPP may inhibit the activation
of the JNK and p38 MAPK pathways, promote cisplatininduced ROS accumulation, suppress stemness, and
enhance the sensitivity of GC to cisplatin.
Conclusions. Up-regulation of LHPP may inhibit the
activation of the JNK and p38 MAPK pathways,
attenuate stemness, and enhance the accumulation of
intracellular ROS, thereby promoting cisplatin-mediated
GC cell apoptosis and enhancing cisplatin sensitivity.
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Citation
Histology and Histopathology Vol. 38, nÂş9 (2023)
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