FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC.
FOXC1 induces cancer stem cell-like properties through upregulation of beta-catenin in NSCLC.
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FOXC1 通过上调 NSCLC 中的 β-catenin 诱导癌症干细胞样特性
DOI：
10.1186/s13046-018-0894-0
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发表时间：
2018-09-06
期刊：
影响因子：
--
通讯作者：
Xu R
中科院分区：
文献类型：
--
作者：
Cao S;Wang Z;Gao X;He W;Cai Y;Chen H;Xu R
越来越多的证据表明，癌症干细胞（CSCs）在肿瘤的发生、发展和治疗中起着至关重要的作用，最近的研究表明叉头盒C1（FOXC 1）与CSCs密切相关。本研究探讨了FOXC 1对非小细胞肺癌（NSCLC）中CSC样特性的调节作用。我们使用UALCANC上的癌症基因组图谱（TCGA）数据库分析了NSCLC中FOXC 1的表达，并在人类蛋白质图谱上进行了NSCLC患者的生存分析。根据CSC标记阳性细胞群、自我更新能力、干细胞相关基因表达、致瘤性和耐药性分析CSC样性质。通过流式细胞术分析CD133+细胞的百分比。通过成球分析检测其自我更新能力。采用实时荧光定量PCR、免疫印迹和免疫组化方法检测mRNA和蛋白水平。基于异种移植物形成测定确定致瘤性，并通过细胞活力和凋亡测定评估FOXC 1对耐药性的影响。荧光素酶报告基因和染色质免疫沉淀（ChIP）分析用于研究FOXC 1与β-连环蛋白启动子的结合。FOXC 1表达在NSCLC组织中升高，与患者生存率呈负相关。FOXC 1基因敲减可降低CD 133+细胞百分比，抑制自我更新能力，降低干细胞相关基因（Oct4、NANOG、SOX 2和ABCG 2）的表达，并抑制NSCLC细胞体内致瘤性。此外，FOXC 1敲低增加顺铂和多西他赛的敏感性和减少吉非替尼耐药性，而FOXC 1过表达增强CSC样特性。荧光素酶报告基因和ChIP检测显示β-连环蛋白是FOXC 1的直接转录靶点。此外，β-连环蛋白的过表达逆转了FOXC 1敲低诱导的CSC样特性抑制，β-连环蛋白的敲低减弱了FOXC 1过表达诱导的CSC样特性。这项研究表明，FOXC 1通过促进β-连环蛋白表达诱导NSCLC中的CSC样特性。研究结果表明，FOXC 1是NSCLC中基于抗CSC治疗的潜在分子靶点。
Accumulating evidence suggests that cancer stem cells (CSCs) play a critical role in tumor initiation, progression and therapy, and recent studies have indicated that Forkhead box C1 (FOXC1) is strongly associated with CSCs. This study investigates the regulatory effects of FOXC1 on CSC-like properties in non-small cell lung cancer (NSCLC). We analyzed FOXC1 expression in NSCLC using the Cancer Genome Atlas (TCGA) database on UALCANC and performed survival analyses of NSCLC patients on Human Protein Atlas. CSC-like properties were analyzed based on CSC marker-positive cell population, self-renewal ability, stemness-related gene expression, tumorigenicity and drug resistance. The percentage of CD133+ cells was analyzed by flow cytometric analysis. Self-renewal ability was detected by sphere-formation analysis. Real-time PCR, western blotting and immunohistochemical staining were employed to detect mRNA and protein levels. Tumorigenicity was determined based on a xenograft formation assay, and effects of FOXC1 on drug resistance were assessed by cell viability and apoptosis assays. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to investigate the binding of FOXC1 to beta-catenin promoter. FOXC1 expression was found to be elevated in NSCLC tissues and negatively correlated with patient survival. FOXC1 knockdown reduced CD133+ cell percentage, suppressed self-renewal ability, decreased expression of stemness-related genes (Oct4, NANOG, SOX2 and ABCG2) and inhibited NSCLC cell tumorigenicity in vivo. Moreover, FOXC1 knockdown increased cisplatin and docetaxel sensitivity and reduced gefitinib resistance, whereas FOXC1 overexpression enhanced CSC-like properties. Luciferase reporter and ChIP assays showed beta-catenin to be a direct transcriptional target of FOXC1. Furthermore, overexpression of beta-catenin reversed the CSC-like property inhibition induced by FOXC1 knockdown, and knockdown of beta-catenin attenuated the CSC-like properties induced by FOXC1 overexpression. This study demonstrates that FOXC1 induces CSC-like properties in NSCLC by promoting beta-catenin expression. The findings indicate that FOXC1 is a potential molecular target for anti-CSC-based therapies in NSCLC.
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影响因子：
11.2
作者：
Hollier BG;Tinnirello AA;Werden SJ;Evans KW;Taube JH;Sarkar TR;Sphyris N;Shariati M;Kumar SV;Battula VL;Herschkowitz JI;Guerra R;Chang JT;Miura N;Rosen JM;Mani SA
通讯作者：
Mani SA
影响因子：
--
作者：
Costanzo R;Piccirillo MC;Sandomenico C;Carillio G;Montanino A;Daniele G;Giordano P;Bryce J;De Feo G;Di Maio M;Rocco G;Normanno N;Perrone F;Morabito A
通讯作者：
Morabito A
DOI：
10.1073/pnas.1601569113
发表时间：
2016-03-15
影响因子：
11.1
作者：
Lay, Kenneth;Kume, Tsutomu;Fuchs, Elaine
通讯作者：
Fuchs, Elaine
影响因子：
4.8
作者：
Kim, Su-Hyeong;Kaschula, Catherine H.;Singh, Shivendra V.
通讯作者：
Singh, Shivendra V.
影响因子：
12.4
作者：
Eramo, A.;Lotti, F.;De Maria, R.
通讯作者：
De Maria, R.