Downregulation of SAFB Sustains the NF-κB Pathway by Targeting TAK1 during the Progression of Colorectal Cancer
Downregulation of SAFB Sustains the NF-κB Pathway by Targeting TAK1 during the Progression of Colorectal Cancer
复制标题
SAFB 下调在结直肠癌进展过程中通过靶向 TAK1 维持 NF-kappa B 通路
DOI：
10.1158/1078-0432.ccr-17-0747
复制
发表时间：
2017-11-15
影响因子：
11.5
通讯作者：
Ding, Yan-Qing
中科院分区：
文献类型：
--
作者：
Jiao, Hong-Li;Ye, Ya-Ping;Ding, Yan-Qing
目的：为探讨支架附着因子B（SAFB）在结直肠癌（CRC）发生发展中的作用及其机制，采用Oncomine肿瘤离群值分析法和175例石蜡包埋的结直肠癌组织中SAFB的表达情况。通过基因本体分析探讨SAFB在结直肠癌进展中的作用机制。采用Western blot、RT-PCR、荧光素酶法和染色质免疫沉淀法检测SAFB对转化生长因子B激活激酶1（TAK 1）和NF-κ B B信号通路的调节作用。使用体外和体内测定研究SAFB在侵袭、转移和血管生成中的作用。结果：SAFB在结直肠癌组织中表达下调，SAFB的低表达与结直肠癌患者的侵袭性表型和生存率显著相关。SAFB的下调通过靶向TAK 1启动子激活NF-κ B信号传导。SAFB的异位表达在体内外均能抑制结直肠癌细胞的侵袭性和转移。TAK 1的过表达可以挽救SAFB过表达细胞的侵袭性特征。此外，SAFB在结直肠癌组织中的表达与TAK 1和NF-κ B相关基因的表达呈负相关。结论：我们的研究结果表明，SAFB调节NF-κ B信号通路的活性在结直肠癌中通过靶向TAK 1。这一新的机制提供了对CRC进展中SAFB和NF-κ B信号通路的全面理解，并表明SAFB-TAK 1-NF-κ B轴是CRC进展中早期治疗干预的潜在靶点。(C)2017年AACR。
Purpose: To investigate the role and the underlying mechanism of scaffold attachment factor B (SAFB) in the progression of colorectal cancer (CRC).Experimental Design: SAFB expression was analyzed in the Cancer Outlier Profile Analysis of Oncomine and in 175 paraffin-embedded archived CRC tissues. Gene Ontology analyses were performed to explore the mechanism of SAFB in CRC progression. Western blot, RT-PCR, luciferase assay, and chromatin immuno-precipitation (ChIP) were used to detect the regulation of transforming growth factor-b-activated kinase 1 (TAK1) and NF-kappa B signaling by SAFB. The role of SAFB in invasion, metastasis, and angiogenesis was investigated using in vitro and in vivo assays. The relationship between SAFB and TAK1 was analyzed in CRC tissues.Results: SAFB was downregulated in CRC tissues, and low expression of SAFB was significantly associated with an aggressive phenotype and poorer survival of CRC patients. The downregulation of SAFB activated NF-kappa B signaling by targeting the TAK1 promoter. Ectopic expression of SAFB inhibited the development of aggressive features and metastasis of CRC cells both in vitro and in vivo. The overexpression of TAK1 could rescue the aggressive features in SAFB-overexpressed cells. Furthermore, the expression of SAFB in CRC tissues was negatively correlated with the expression of TAK1-and NF-kappa B-related genes.Conclusions: Our results show that SAFB regulated the activity of NF-kappa B signaling in CRC by targeting TAK1. This novel mechanism provides a comprehensive understanding of both SAFB and the NF-kappa B signaling pathway in the progression of CRC and indicates that the SAFB-TAK1-NF-kappa B axis is a potential target for early therapeutic intervention in CRC progression. (C) 2017 AACR.