Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7
Silencing of circRACGAP1 sensitizes gastric cancer cells to apatinib via modulating autophagy by targeting miR-3657 and ATG7
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DOI：
10.1038/s41419-020-2352-0
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发表时间：
2020-03-05
影响因子：
9
通讯作者：
Shu, Yongqian
中科院分区：
文献类型：
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作者：
Ma, Ling;Wang, Zhangding;Shu, Yongqian
阿帕替尼III期试验的积极结果为晚期胃癌(GC)的治疗带来了新的曙光。然而，在安全性方面，阿帕替尼的毒性可能导致剂量改变或治疗中断。因此，迫切需要适当的干预来帮助患者从阿帕替尼治疗中受益。在这项研究中，我们发现阿帕替尼通过上调ATG7的表达来促进自噬激活，而自噬抑制增强了阿帕替尼诱导的细胞凋亡。通过对GC异种移植模型的microRNA和环状RNA测序分析，我们证明了CircACGAP1作为miR-3657的内源性海绵抑制其活性，并进一步上调ATG7的表达。沉默CircRACGAP1抑制阿帕替尼诱导的自噬，而这一自噬被miR-3657拯救。此外，在体外和体内，CircACGAP1的敲除通过抑制自噬而使GC细胞对阿帕替尼增敏。这些发现首次证明，CircRACGAP1-miR-3657-ATG7轴介导了一种新的调控途径，对调节GC中阿帕替尼的敏感性至关重要。因此，特异性阻断CircACGAP1可能成为降低阿帕替尼毒副作用、提高其治疗效果的潜在治疗策略。
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 therapeutic effect in human GC.