Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A
Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A
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DOI：
10.1016/j.ebiom.2019.07.004
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发表时间：
2019-07-01
期刊：
影响因子：
11.1
通讯作者：
Ebert, Matthias P.
中科院分区：
文献类型：
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作者：
Burgermeister, Elke;Battaglin, Francesca;Ebert, Matthias P.
背景：在耐药转移性结直肠癌（mCRC）中，迫切需要鉴定新的生物标志物和开发新的、可靶向的易感性环境。aryl -碳氢化合物受体-核易位子样（ARNTL/BMAL1）是一种生物钟调节的转录因子，可促进参与血管生成和肿瘤进展的基因表达。我们假设BMAL1增加血管内皮生长因子A VEGFA基因的表达，从而赋予抗血管生成治疗贝伐单抗（Beva）的耐药性，贝伐单抗是临床上用于中和VEGFA的抗体。方法：采用PCR和免疫组化检测小鼠（C57BL/6 J (Apcmin/+)） BMAL1的表达；BALB/c （nu/nu）异种移植物)和结直肠癌患者联合Beva化疗。应用dna芯片技术分析临床样本BMAL1单核苷酸基因多态性（snp）。利用比色生长、dna结合和报告基因分析研究了BMAL1在人结直肠癌细胞系中的功能。结果：在小鼠crc中，BMAL1高表达与Beva治疗的临床前反应差相关。在结直肠癌患者肿瘤（n = 74）中，BMAL1高表达与临床对Beva联合化疗无反应（*p = 0.0061）和无进展生存期（PFS）降低相关[*p = 0.0223，危险比(HR)= 1.69]。BMAL1 snp也与较短的PFS （rs7396943, rs7938307, rs2279287）和总生存期（OS）相关[rs11022780， *p = 0.014, HR = 1.61]。在机制上，核受体亚家族-1组- d成员-1 （NR1D1/REVERBA）结合了VEGFA基因启动子中一个672 bp的retinoic - acid - receptor - related - orphan - receptor - alpha - responsive元件（RORE），该元件邻近BMAL1 dna结合基序（E-box），导致VEGFA合成增加和人CRC细胞系增殖。结论：BMAL1与结直肠癌患者的Beva耐药有关。抑制REVERBA-BMAL1信号可能会阻止抗血管生成治疗的耐药性。(C) 2019作者。Elsevier B.V.出版
Background: The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor- Nuclear-Translocator-Like (ARNTL/BMAL1) is a circadian clock-regulated transcription factor promoting expression of genes involved in angiogenesis and tumour progression. We hypothesised that BMAL1 increases expression of the vascular endothelial growth factor A VEGFA gene and, thereby, confers resistance to anti-angiogenic therapy with bevacizumab (Beva), a clinically used antibody for neutralization of VEGFA.Methods: PCR and immunohistochemistry were employed to assess BMAL1 expression in mice (C57BL/6 J (Apcmin/+); BALB/c (nu/nu) xenografts) and CRC patients under combination chemotherapy with Beva. BMAL1 single nucleotide gene polymorphisms (SNPs) were analysed by DNA-microarray in clinical samples. BMAL1 functions were studied in human CRC cell lines using colorimetric growth, DNA-binding and reporter assays.Findings: In murine CRCs, high BMAL1 expression correlated with poor preclinical response to Beva treatment. In CRC patients' tumours (n = 74), high BMAL1 expression was associated with clinical non-response to combination chemotherapy with Beva (*p = .0061) and reduced progression-free survival (PFS) [*p = .0223, Hazard Ratio (HR)= 1.69]. BMAL1 SNPs also correlated with shorter PFS (rs7396943, rs7938307, rs2279287) and overall survival (OS) [rs11022780, *p = .014, HR = 1.61]. Mechanistically, Nuclear-Receptor-Subfamily-1-Group-D-Member-1 (NR1D1/REVERBA) bound a - 672 bp Retinoic-Acid-Receptor-Related-Orphan-Receptor-Alpha-responsive-element (RORE) adjacent to a BMAL1 DNA-bindingmotif (E-box) in the VEGFA gene promoter, resulting in increased VEGFA synthesis and proliferation of human CRC cell lines.Interpretation: BMAL1 was associated with Beva resistance in CRC. Inhibition of REVERBA-BMAL1 signallingmay prevent resistance to anti-angiogenic therapy. (C) 2019 The Authors. Published by Elsevier B.V.