Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7.

Cell Death & Disease
Ling MaYongqian Shu

Abstract

The positive results of the apatinib phase III trial have cast new light on treatment for patients with advanced gastric cancer (GC). However, in terms of safety, apatinib toxicities may lead to a dose modification or treatment interruption. Therefore, proper intervention is urgently needed to help patients benefit from apatinib treatment. In this study, we found that apatinib promoted autophagy activation via upregulation of ATG7 expression and autophagy inhibition enhanced apatinib-induced apoptosis. With microRNA and circular RNA-sequencing analyses of GC xenograft models, we demonstrated that circRACGAP1 functioned as an endogenous sponge for miR-3657 to inhibit its activity and further upregulate ATG7 expression. Silencing of circRACGAP1 inhibited apatinib-induced autophagy, which was rescued by miR-3657. Moreover, knockdown of circRACGAP1 sensitized GC cells to apatinib via autophagy inhibition in vitro and in vivo. These findings provided the first evidence that the circRACGAP1-miR-3657-ATG7 axis mediates a novel regulatory pathway critical for the regulation of apatinib sensitivity in GC. Thus, specific blockage of circRACGAP1 may be a potential therapeutic strategy to reduce the toxicities of apatinib and enhance its t...Continue Reading

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Citations

Jul 24, 2020·Journal of Clinical Laboratory Analysis·Xukun LvShuliang Li
Jul 11, 2020·Chinese Medical Journal·Si-Ran WuYong-Quan Shi
Aug 8, 2020·Molecular Cancer·Shuo MaShaoqing Ju
Jul 21, 2020·BioMed Research International·Jiafeng OuyangGuoqing Li
Jan 8, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Soudeh Ghafouri-FardMohammad Taheri
Feb 3, 2021·Autophagy·Soudeh Ghafouri-FardMohammad Taheri
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May 13, 2021·Cell Death & Disease·Lorena VerduciGiovanni Blandino
Jun 8, 2021·Molecular Therapy Oncolytics·Zhixia ZhouPeifeng Li
Jul 6, 2021·Frontiers in Genetics·Liora YesharimMaryam Abiri

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Methods Mentioned

BETA
xenografts
PCR
circRNA-seq
xenograft
fluorescence microscopy
electron
RNA Assay
transfection
flow cytometry
RNA-seq

Software Mentioned

Cell Quest
TargetScan
miRanda
Zeiss AIM
circRNA Finder

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