Stearoyl-CoA-desaturase-1 regulates gastric cancer stem-like properties and promotes tumour metastasis via Hippo/YAP pathway
Stearoyl-CoA-desaturase-1 regulates gastric cancer stem-like properties and promotes tumour metastasis via Hippo/YAP pathway
复制标题
硬脂酰辅酶A去饱和酶-1通过Hippo/YAP途径调节胃癌干细胞样特性并促进肿瘤转移
DOI：
10.1038/s41416-020-0827-5
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发表时间：
2020-04-30
影响因子：
8.8
通讯作者：
Chen, Lin
中科院分区：
文献类型：
--
作者：
Gao, Yunhe;Li, Jiyang;Chen, Lin
背景硬脂酰辅酶A去饱和酶-1(Scd1)在多种癌症中起重要作用。我们先前的研究发现，SCD1在原代胃癌干细胞(GCSCs)中有明显的过表达，但其功能尚不清楚。方法通过球体形成法和流式细胞术稳定地建立了三种原代GCSCs。蛋白质定量和生物信息学分析揭示差异蛋白质图谱。以慢病毒为基础的小干扰RNA(SiRNA)敲除和药理抑制方法研究了SCD1在体内外调节GCSCs干性和肿瘤转移能力方面的功能和分子机制。结果SCD1可增加GCSCs的数量，但其抑制或siRNA敲除可减弱GCSCs的干性，包括化疗耐药性和球体形成能力。此外，在体外和体内，抑制SCD1逆转了上皮向间充质的转变，降低了GC转移的几率。GCSCs中SCD1的下调与HIPPO途径中的关键蛋白YAP的表达有关，并且核YAP的转位也被SCD1值的降低所阻断。结论SCD1通过HIPPO/YAP途径促进GCSC的干化。靶向SCD1可能是一种新的治疗策略，特别是在抑制GC转移和增敏化疗方面。
BackgroundStearoyl-CoA desaturase-1 (SCD1) is reported to play essential roles in cancer stemness among several cancers. Our previous research revealed significant overexpression of SCD1 in primary gastric cancer stem cells (GCSCs), with its functional role still unknown.MethodsWe stably established three primary GCSCs by sphere-forming assays and flow cytometry. Protein quantification and bioinformatics analysis were performed to reveal the differential protein pattern. Lentivirus-based small-interfering RNA (siRNA) knockdown and pharmacological inhibition approaches were used to characterise the function and molecular mechanism role of SCD1 in the regulation of GC stemness and tumour metastasis capacity both in vitro and in vivo.ResultsSCD1 was found to increase the population of GCSCs, whereas its suppression by an SCD1 inhibitor or knockdown by siRNA attenuated the stemness of GCSCs, including chemotherapy resistance and sphere-forming ability. Furthermore, SCD1 suppression reversed epithelial-to-mesenchymal transition and reduced the GC metastasis probability both in vitro and in vivo. Downregulation of SCD1 in GCSCs was associated with the expression of Yes-associated protein (YAP), a key protein in the Hippo pathway, and nuclear YAP translocation was also blocked by the SCD1 decrease.ConclusionsSCD1 promotes GCSC stemness through the Hippo/YAP pathway. Targeting SCD1 might be a novel therapeutic strategy, especially to suppress GC metastasis and sensitise chemotherapy.