Down-Regulation of Activating Transcription Factor 3 (ATF3) in Hepatoblastoma and Its Relationship with Ferroptosis

Abstract

Purpose The molecular mechanisms and signal pathways of ferroptosis in hepatoblastoma (HB) have not yet been clarified. In previous studies, activating transcription factor 3 (ATF3) was reported to be correlated with several tumors, but the clinical significance of ATF3 has never been determined. Herein, we investigated the clinicopathological value and mechanisms of ATF3 in regulating ferroptosis in HB. Methods The mRNA microarray and RNA-sequencing data of 402 samples from our hospital and public databases were used to estimate ATF3 expression and assess its clinical role in HB. The standard mean difference (SMD) and summary receiver operating characteristic curves were utilized to judge the discrimination ability of ATF3 between HB and non-HB liver tissues. We examined the expression variation of ATF3 in HB cells after the treatment with erastin. We also predicted the target genes of ATF3 as a transcriptional factor from public Chromatin Immunoprecipitation-sequencing data and selected the ferroptosis-related genes for a signaling pathway analysis. Results In ten series, the pooled SMD for ATF3 was −0.91, demonstrating that ATF3 expression was predominantly lower in HB than in non-HB liver tissues. ATF3 down-regulation showed moderate potential to distinguish HB from non-HB liver tissues (area under curves = 0.83, 95% confidence interval = 0.79–0.86). Altogether, 4855 putative targets of ATF3 as a transcriptional factor were collected, among which, 60 genes were ferroptosis-related. Conclusion The down-regulated ATF3 expression may play a vital role in the occurrence of HB possible partially by regulating ferroptosis.

Ferroptosis regulator NOS2 is closely associated with the prognosis and cell malignant behaviors of hepatoblastoma: a bioinformatic and in vitro study

“…One study revealed that N6-methyladenosine modification enhances HB resistance to ferroptosis by inhibiting SLC7A11, thereby mediating therapeutic resistance ( 12 ). Another bioinformatic study reported that the ferroptosis driver ATF3 may serve as a biomarker for predicting HB occurrence ( 13 ).…”

Analysis and verification of ferroptosis-related genes in pediatric hepatoblastoma

“…For instance, Liu et al revealed that m6-methyladenosine modi cation in HB could enhance ferroptosis resistance of SLC7A11, providing a potential strategy for HB therapy14 . Li et al exhibited that down-regulated activating transcription factor 3 (ATF3) play a vital role in HB development by regulating ferroptosis15 . However, there are few research works on whether speci c ferroptosis-related genes regulate HB pathogenesis and prognosis at present.…”