FIBP knockdown attenuates growth and enhances chemotherapy in colorectal cancer via regulating GSK3β-related pathways.
FIBP knockdown attenuates growth and enhances chemotherapy in colorectal cancer via regulating GSK3β-related pathways.
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FIBP 敲低可通过调节 GSK3beta 相关途径来减弱结直肠癌的生长并增强化疗效果。
DOI：
10.1038/s41389-018-0088-9
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发表时间：
2018-10-02
期刊：
影响因子：
6.2
通讯作者：
Lu L
中科院分区：
文献类型：
--
作者：
Huang YF;Niu WB;Hu R;Wang LJ;Huang ZY;Ni SH;Wang MQ;Yang Y;Huang YS;Feng WJ;Xiao W;Zhu DJ;Xian SX;Lu L
结直肠癌干细胞（CSCs）具有自我更新能力和增殖基因的高表达，是结直肠癌化疗耐药的重要原因。我们的目标是通过全面的生物信息学筛选和基因功能的实验确认来确定CRC化疗耐药的分子机制。我们发现FGF 1细胞内结合蛋白（FIB）的高表达与大肠癌患者的化疗耐药和不良预后相关。因此，建立了具有高表达干细胞标志物CD 44和CD 133的化学抗性CRC细胞系HCT 116-CSC用于进一步的表型测试。在体内和体外，FIB敲低抑制CRC细胞的增殖，增强化疗效果，并减弱干细胞标记物。通过RNA-seq和基因集富集分析，我们确定了细胞周期蛋白D1作为FIB调节细胞周期进程和增殖的关键下游靶点。此外，FIB与GSK 3 β结合，抑制其Tyr 216磷酸化，并激活HCT 116-CSC中的β-catenin/TCF/细胞周期蛋白D1信号传导。额外的GSK 3 β敲低逆转了HCT 116-CSC中FIB沉默诱导的增殖抑制和干性标志物表达降低。此外，DNA甲基化分析表明，FIB通过依赖于GSK 3 β但不依赖于β-catenin信号传导的甲基化活性调节CRC细胞的干性。我们的数据阐明了FIB作为通过抑制GSK 3 β相关信号传导治疗化疗耐药CRC的新型治疗靶点的潜力。
Colorectal cancer stem cells (CSCs), characterized by self-renewal ability and high expression of proliferative genes, contribute to the chemoresistance of colorectal cancer (CRC). We aimed to identify the molecular mechanisms underlying CRC chemoresistance through comprehensive bioinformatics screenings and experimental confirmation of gene functions. We found that high expression of FGF1 intracellular binding protein (FIBP) was correlated with chemoresistance and poor prognosis in CRC patients. Therefore, the chemoresistant CRC cell line HCT116-CSC with high expression of the stem cell markers CD44 and CD133 was established for further phenotypic tests. FIBP knockdown inhibited proliferation, enhanced chemotherapy effects, and attenuated the stemness markers of CRC cells in vivo and in vitro. Through RNA-seq and gene set enrichment analysis, we identified cyclin D1 as a key downstream target in FIBP-regulated cell cycle progression and proliferation. Moreover, FIBP bound to GSK3β, inhibited its phosphorylation at Tyr216, and activated β-catenin/TCF/cyclin D1 signaling in HCT116-CSCs. Additional GSK3β knockdown reversed the FIBP silencing-induced inhibition of proliferation and decreased stemness marker expression in HCT116-CSCs. Furthermore, DNA methylation profiling suggested that FIBP regulated the stemness of CRC cells via methylation activity that was dependent on GSK3β but independent of β-catenin signaling. Our data illuminate the potential of FIBP as a novel therapeutic target for treating chemoresistant CRC through inhibition of GSK3β-related signaling.
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影响因子：
4.6
作者：
Leis, H;Segrelles, C;Paramio, JM
通讯作者：
Paramio, JM
影响因子：
4.8
作者：
Popkie, Anthony P.;Zeidner, Leigh C.;Phiel, Christopher J.
通讯作者：
Phiel, Christopher J.
荷兰队列研究中散发性结直肠癌中 APC、CTNNB1 和 K-ras 基因的突变以及 hMLH1 的表达。
影响因子：
3.8
作者：
Lüchtenborg M;Weijenberg MP;Wark PA;Saritas AM;Roemen GM;van Muijen GN;de Bruïne AP;van den Brandt PA;de Goeij AF
通讯作者：
de Goeij AF
影响因子：
3.3
作者：
Meredith GD;D'Ippolito A;Dudas M;Zeidner LC;Hostetter L;Faulds K;Arnold TH;Popkie AP;Doble BW;Marnellos G;Adams C;Wang Y;Phiel CJ
通讯作者：
Phiel CJ
影响因子：
8
作者：
Jeter, C. R.;Liu, B.;Liu, X.;Chen, X.;Liu, C.;Calhoun-Davis, T.;Repass, J.;Zaehres, H.;Shen, J. J.;Tang, D. G.
通讯作者：
Tang, D. G.