Circular CPM promotes chemoresistance of gastric cancer via activating PRKAA2-mediated autophagy.
Circular CPM promotes chemoresistance of gastric cancer via activating PRKAA2-mediated autophagy.
复制标题
循环CPM通过激活PRKAA2介导的自噬促进胃癌化疗耐药
DOI：
10.1002/ctm2.708
复制
发表时间：
2022-01
影响因子：
10.6
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Fang L;Lv J;Xuan Z;Li B;Li Z;He Z;Li F;Xu J;Wang S;Xia Y;Jiang T;Zhang L;Wang L;Zhang D;Xu H;Yang L;Xu Z;Wang W
化疗可以显著提高晚期胃癌（GC）患者的无病生存期和总生存期。5-氟尿嘧啶（5-FU）是临床常用的晚期胃癌一线化疗药物，可单独使用或与铂类药物联合使用。然而，其疗效因化疗耐药性而显着减弱，这与患者的生存率低有关。近年来，有证据表明自噬的失调可能是肿瘤耐药的原因之一，而环状RNA（circRNA）也参与了肿瘤耐药的形成。然而，circRNA是否通过自噬参与5-FU化疗耐药性仍然很大程度上未知。在GC中进行RNA测序技术和生物信息学分析。桑格测序、放线菌素D测定和RNase R测定证实了环状CPM（circCPM）的环状结构。采用多种细胞系模型和动物模型，在体外和体内探索相关功能。应用定量真实的-时间PCR（qRT-PCR）、荧光原位杂交、核糖核酸（RNA）下拉分析、RNA结合蛋白免疫沉淀分析和荧光素酶报告基因分析来探索相关通路。circCPM在5-FU耐药GC细胞系和组织中上调。此外，circCPM高表达与生存率低呈正相关。沉默circCPM大大提高了体外和体内的化疗敏感性。从机制上讲，它直接与细胞质中的miR-21 - 3 p结合，因此增加了PRKAA 2的表达，有助于自噬和化疗耐药性的激活。我们的研究结果表明，circCPM通过靶向PRKAA 2在调节GC自噬和5-FU耐药性方面起着至关重要的作用。为评价胃癌的疗效和逆转5-FU耐药提供了新的理论依据。CircCPM在5-FU耐药胃癌细胞和组织中上调。CircCPM通过充当miR-21 - 3 p的海绵来调节自噬，从而上调PRKAA 2的表达。CircCPM通过miR-21 - 3 p/PRKAA 2轴调节胃癌5-FU化疗耐药性
Chemotherapy can significantly improve the disease‐free survival and overall survival of patients with advanced gastric cancer (GC). 5‐fluorouracil (5‐FU) is frequently applied in the clinic, acting as a first‐line chemotherapy drug of advanced GC, which could be used alone or combining platinum drugs. However, its efficacy is significantly attenuated by chemoresistance, which is associated with patients’ poor survival. Recently, there is evidence suggesting that dysregulation of autophagy may contribute to drug resistance in cancer, and circular RNAs (circRNAs) also take part in chemoresistance. However, whether circRNAs participate in 5‐FU chemoresistance through autophagy remains largely unknown. RNA sequencing technologies and bioinformatics analysis were performed in GC. Sanger sequencing, Actinomycin D assay and RNase R assay confirmed the circular structure of circular CPM (circCPM). Various cell line models and animal models were used to explore related functions in vitro and in vivo. Quantitative Real‐time PCR (qRT‐PCR), fluorescence in situ hybridization, ribonucleic acid; (RNA) pulldown assays, RNA binding protein immunoprecipitation assays and Luciferase reporter assays were applied to explore involved pathways. circCPM was up‐regulated in 5‐FU resistant GC cell lines and tissue. Moreover, high circCPM expression is positively associated with poor survival. Silencing circCPM greatly improved chemosensitivity in vitro and in vivo. Mechanistically, it directly binds to miR‐21‐3p in the cytoplasm and therefore increases the expression of PRKAA2, contributing to the activation of autophagy and chemoresistance. Our results reveal that circCPM has a crucial role in regulating GC autophagy and 5‐FU resistance by targeting PRKAA2. It may function as a new theory basis for assessing the curative effect of GC and reversing 5‐FU chemoresistance. CircCPM is up‐regulated in 5‐FU resistant gastric cancer cells and tissues. CircCPM modulates autophagy by working as a sponge of miR‐21‐3p, thereby up‐regulating PRKAA2 expression. CircCPM regulates gastric cancer 5‐FU chemoresistance through the miR‐21‐3p/ PRKAA2 axis.
登录
查看更多内容
MicroRNA-148a-3p通过线粒体裂变诱导和细胞保护性自噬抑制增强顺铂对胃癌的细胞毒性
影响因子：
9.7
作者：
Li B;Wang W;Li Z;Chen Z;Zhi X;Xu J;Li Q;Wang L;Huang X;Wang L;Wei S;Sun G;Zhang X;He Z;Zhang L;Zhang D;Xu H;El-Rifai W;Xu Z
通讯作者：
Xu Z
影响因子：
15.9
作者：
Alissafi, Themis;Hatzioannou, Aikaterini;Verginis, Panayotis
通讯作者：
Verginis, Panayotis
肿瘤细胞粘附后内皮细胞差异表达基因分析以及 PRKAA2 和 miR-124-3p 的作用
影响因子：
5.5
作者：
Pan Y;Abdureyim M;Yao Q;Li X
通讯作者：
Li X
影响因子：
254.7
作者：
McCracken, Melissa;Olsen, Miho;Ward, Elizabeth
通讯作者：
Ward, Elizabeth
影响因子：
2.5
作者：
通讯作者：
--