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

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

KEYWORDS:

• NR2F6
• overexpression
• hepatoblastoma
• residual tumor
• ablation

Highlight:

1. This is the first study to indicate the upregulated expression of NR2F6 in hepatoblastoma with multiregion and multisource samples.

2. A higher level of NR2F6 was found in residual hepatoblastoma xenografts receiving incomplete ablation.

3. Upregulated NR2F6 contributes to the dysregulation of lipid metabolism in residual hepatoblastoma.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data supporting the results were obtained from several public databases (GEO, SRA, and ArrayExpress) and in-house nude mouse xenograft experiment.

E-MEXP-1852(https://www.ebi.ac.uk/arrayexpress/experiments/E-MEXP-1852/);

GSE104766(https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi);

GSE131329(https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi);

GSE132037(https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi);

GSE133039(https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi);

GSE151347(https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi)

GSE81928(https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi);

GSE89775(https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi)

Supplementary material

Supplemental data for this article can be accessed here

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (Grant nos. NSFC81860319 and NSFC81960329) as well as Guangxi Degree and Postgraduate Education Reform and Development Research Projects, China (JGY2019050), and Guangxi Zhuang Autonomous Region Health Commission Self-Financed Scientific Research Project (Z20200317 and Z20200396).