Incomplete thermal ablation-induced up-regulation of transcription factor nuclear receptor subfamily 2, group F, member 6 (NR2F6) contributes to the rapid progression of residual liver tumor in hepatoblastoma.
Incomplete thermal ablation-induced up-regulation of transcription factor nuclear receptor subfamily 2, group F, member 6 (NR2F6) contributes to the rapid progression of residual liver tumor in hepatoblastoma.
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不完全热消融诱导的转录因子核受体亚家族2，F组，成员6（NR2F6）的上调有助于肝母细胞瘤中残留肝脏肿瘤的快速进展
DOI：
10.1080/21655979.2021.1945521
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发表时间：
2021-12
期刊：
影响因子：
4.9
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Pang JS;Wen DY;He RQ;Chen G;Lin P;Li JH;Zhao YJ;Wu LY;Chen JH;He Y;Qin LT;Chen JB;Li Y;Yang H
摘要肝母细胞瘤是儿童常见的恶性肿瘤。虽然手术切除被认为是肝母细胞瘤的一线治疗方法，但相对较大的患者群体已经失去了手术的首选机会。局部消融的管理能够局部控制肿瘤，但存在消融不充分、肿瘤残留和快速进展的缺陷。在这项研究中，我们整合了219例肝母细胞瘤和121例非癌肝组织，以评估NR2F6的表达，其中肝母细胞瘤中的NR2F6水平高于非癌肝，标准均数差（SMD）为1.04（95%CI：0.79，1.29）。NR 2F6的过表达似乎也是区分肝母细胞瘤组织与非癌肝脏组织的有效指标，其汇总AUC为0.90，汇总灵敏度为0.76，汇总特异性为0.89。有趣的是，裸鼠异种移植物提供了直接证据，与未治疗的肝母细胞瘤相比，在残留肿瘤中也检测到过表达的NR2F6。结合HepG2细胞中的染色质免疫沉淀结合数据和HepG2异种移植物的转录组分析来鉴定由NR2F6调控的靶基因。我们最终在不完全消融的残余肿瘤中筛选出150个NR2F6的新靶基因，这些基因似乎与脂质代谢相关通路的生物调节有关。因此，靶向NR2F6在治疗不完全消融后残留复发性肝母细胞瘤方面具有治疗前景。图形摘要
ABSTRACT Hepatoblastoma is a kind of extreme malignancy frequently diagnosed in children. Although surgical resection is considered as the first-line treatment for hepatoblastoma, a relatively large population of patients have lost the preferred opportunity for surgery. Administration of locoregional ablation enables local tumor control but with the deficiency of insufficient ablation, residual tumor, and rapid progression. In this study, we integrated 219 hepatoblastoma and 121 non-cancer liver tissues to evaluate the expression of NR2F6, from which a higher NR2F6 level was found in hepatoblastoma compared with non-cancer livers with a standard mean difference (SMD) of 1.04 (95% CI: 0.79, 1.29). The overexpression of NR2F6 also appeared to be an efficient indicator in distinguishing hepatoblastoma tissues from non-cancer liver tissues from the indication of a summarized AUC of 0.90, with a pooled sensitivity of 0.76 and a pooled specificity of 0.89. Interestingly, nude mouse xenografts provided direct evidence that overexpressed NR2F6 was also detected in residual tumor compared to untreated hepatoblastoma. Chromatin immunoprecipitation-binding data in HepG2 cells and transcriptome analysis of HepG2 xenografts were combined to identify target genes regulated by NR2F6. We finally selected 150 novel target genes of NR2F6 in residual tumor of incomplete ablation, and these genes appeared to be associated with the biological regulation of lipid metabolism-related pathway. Accordingly, targeting NR2F6 holds a therapeutic promise in treating residual recurrent hepatoblastoma after incomplete ablation. GRAPHICAL ABSTRACT